# NM_198291.3(SRC):c.350C>T (p.Thr117Ile)

https://sugi.bio/variant/src-p-thr117ile

## Summary

**SRC p.Thr117Ile (c.350C>T)** is classified **Uncertain significance** in SRC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.5645); Very rare (popmax 0.00333%, amr); Associated with intellectual disability, autosomal dominant 40.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the SRC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to intellectual disability, autosomal dominant 40.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013539/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SRC](https://sugi.bio/atlas/gene/SRC/) |
| Protein change (HGVS p.) | p.Thr117Ile |
| Coding change (HGVS c.) | c.350C>T |
| MANE Select transcript | [NM_198291](https://www.ncbi.nlm.nih.gov/nuccore/NM_198291) |
| Variant type | single nucleotide variant |
| Location | chr20:37386174-37386174 (GRCh38) |
| ClinVar | [VCV4278080](https://www.ncbi.nlm.nih.gov/clinvar/variation/4278080/) |

**All HGVS expressions:** `LRG_1018:g.46490C>T`, `LRG_1018t1:c.350C>T`, `NC_000020.10:g.36014577C>T`, `NC_000020.11:g.37386174C>T`, `NG_023033.1:g.46490C>T`, `NM_005417.5:c.350C>T`, `NM_198291.3:c.350C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.5645)
- REVEL 0.285 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.626 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.628, GERP 1.07, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.35** across the covering region of the MANE Select transcript (37,386,085–37,393,917), spanning 7,832 bp — the region is depleted of missense variation. Chi-square p 1.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for SRC (1,274 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/60,000 in the highest group · 6/1,613,922 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,000 |
| South Asian | 0.0022% | 45,542 |
| European (non-Finnish) | 0.00017% | 589,957 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SRC** population constraint: LOEUF 0.383, pLI 0.99997, missense-Z 2.8596. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **thrombocytopenia 6** — Moderate (AD)

## Protein context {#protein}

Residue **117** lies in the sh3 domain.

AlphaFold model confidence (whole protein): pLDDT 84.59, 68% of residues very-high.

**79 experimental structure(s)** (PDB): [1A07](https://www.rcsb.org/structure/1A07), [1A08](https://www.rcsb.org/structure/1A08), [1A09](https://www.rcsb.org/structure/1A09), [1A1A](https://www.rcsb.org/structure/1A1A), [1A1B](https://www.rcsb.org/structure/1A1B), [1A1C](https://www.rcsb.org/structure/1A1C) — incl. mutant structure 1KSW.

## What this gene does {#gene-function}

*Describes the biological roles of SRC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SRC's established molecular role includes protein kinase activity. p.Thr117Ile falls in the sh3 domain. In Reactome, SRC is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **InlA-mediated entry of Listeria monocytogenes into host cells**.

**Disease mechanism (Reactome):** SRC loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955).

### Pathways affected {#pathways}

SRC participates in **70 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | other |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | other |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Downregulation of ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1253288) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | curated |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | curated |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | curated |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [p130Cas linkage to MAPK signaling for integrins](https://reactome.org/content/detail/R-HSA-372708) | curated |
| [ADP signalling through P2Y purinoceptor 1](https://reactome.org/content/detail/R-HSA-418592) | other |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | electronic |
| [Activated NTRK3 signals through PI3K](https://reactome.org/content/detail/R-HSA-9603381) | electronic |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | other |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | other |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | other |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | other |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |
| [EPH-Ephrin signaling](https://reactome.org/content/detail/R-HSA-2682334) | other |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | other |
| [EPHA-mediated growth cone collapse](https://reactome.org/content/detail/R-HSA-3928663) | other |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | other |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | other |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | other |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | electronic |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | other |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [Netrin mediated repulsion signals](https://reactome.org/content/detail/R-HSA-418886) | electronic |
| [PECAM1 interactions](https://reactome.org/content/detail/R-HSA-210990) | other |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | other |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | other |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Receptor Mediated Mitophagy](https://reactome.org/content/detail/R-HSA-8934903) | other |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | other |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | other |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | electronic |
| [Regulation of commissural axon pathfinding by SLIT and ROBO](https://reactome.org/content/detail/R-HSA-428542) | electronic |
| [Regulation of gap junction activity](https://reactome.org/content/detail/R-HSA-191650) | other |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | electronic |
| [Signal regulatory protein family interactions](https://reactome.org/content/detail/R-HSA-391160) | other |
| [Signaling by ALK](https://reactome.org/content/detail/R-HSA-201556) | other |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by EGFR](https://reactome.org/content/detail/R-HSA-177929) | other |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | other |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | other |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | other |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | other |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | other |
| [p38MAPK events](https://reactome.org/content/detail/R-HSA-171007) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein kinase activity, protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, signaling receptor binding, integrin binding, phospholipase activator activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, transforming growth factor beta receptor signaling pathway, integrin-mediated signaling pathway, regulation of epithelial cell migration, positive regulation of epithelial cell migration, peptidyl-tyrosine phosphorylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[intellectual disability, autosomal dominant 40](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-40/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 40, NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, IMPAIRED LANGUAGE, AND DYSMORPHIC FEATURES.

## Similar variants {#similar}

Related SRC variant pages (same residue, condition, or type): [SRC p.Glu527Lys](/variant/src-p-glu527lys), [SRC p.Glu492Lys](/variant/src-p-glu492lys), [SRC c.1117-180C>T](/variant/src-c-1117-minus-180c-t), [SRC c.1117-9C>T](/variant/src-c-1117-minus-9c-t), [SRC c.1271-55=](/variant/src-c-1271-minus-55), [SRC c.449+9C>T](/variant/src-c-449-plus-9c-t), [SRC c.553+8C>T](/variant/src-c-553-plus-8c-t), [SRC c.554-5C>T](/variant/src-c-554-minus-5c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4278080). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*