# NM_021947.3(SRR):c.520G>T (p.Val174Phe)

https://sugi.bio/variant/srr-p-val174phe

## Summary

**SRR p.Val174Phe (c.520G>T)** is classified **Uncertain significance** in SRR (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.2503); Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the SRR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SRR](https://sugi.bio/atlas/gene/SRR/) |
| Protein change (HGVS p.) | p.Val174Phe |
| Coding change (HGVS c.) | c.520G>T |
| MANE Select transcript | [NM_021947](https://www.ncbi.nlm.nih.gov/nuccore/NM_021947) |
| Variant type | single nucleotide variant |
| Location | chr17:2321542-2321542 (GRCh38) |
| ClinVar | [VCV3449491](https://www.ncbi.nlm.nih.gov/clinvar/variation/3449491/) |

**All HGVS expressions:** `NC_000017.10:g.2224836G>T`, `NC_000017.11:g.2321542G>T`, `NM_001304803.1:c.73G>T`, `NM_021947.3:c.520G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2503)
- REVEL 0.756 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.326 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor loss** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.806, GERP -0.127, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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 0.92** across the covering region of the MANE Select transcript (2,315,561–2,323,870), spanning 8,309 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.47**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.49** (loss), gain 0.08 / loss 0.49. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00428% · FAF99 0.00295% · 1/6,060 in the highest group · 61/1,613,932 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| Admixed American | 0.01% | 9,998 |
| South Asian | 0.00439% | 22,769 |
| European (non-Finnish) | 0.0039% | 25,652 |
| African / African-American | 0.00267% | 37,452 |
| East Asian | 0.00223% | 44,896 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |

*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}

**SRR** population constraint: LOEUF 0.864, pLI 0.00036232, missense-Z 0.97016. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.95, 88% of residues very-high.

**11 experimental structure(s)** (PDB): [3L6B](https://www.rcsb.org/structure/3L6B), [3L6R](https://www.rcsb.org/structure/3L6R), [5X2L](https://www.rcsb.org/structure/5X2L), [6SLH](https://www.rcsb.org/structure/6SLH), [6ZSP](https://www.rcsb.org/structure/6ZSP), [6ZUJ](https://www.rcsb.org/structure/6ZUJ).

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

*Describes the biological roles of SRR (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:** SRR's established molecular role includes magnesium ion binding.


### Pathways affected {#pathways}

SRR participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Serine metabolism](https://reactome.org/content/detail/R-HSA-977347) | other |

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

**Molecular function:** magnesium ion binding, L-serine ammonia-lyase activity, ATP binding, PDZ domain binding, pyridoxal phosphate binding, serine racemase activity.

**Biological process:** L-serine metabolic process, response to lipopolysaccharide, pyruvate biosynthetic process, obsolete D-serine metabolic process, D-serine biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-10.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-10 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not specified, Thyroid cancer, nonmedullary, 1, AllHighlyPenetrant.

## Similar variants {#similar}

Related SRR variant pages (same residue, condition, or type): [SRR p.Ala167Thr](/variant/srr-p-ala167thr), [SRR p.Arg58His](/variant/srr-p-arg58his), [SRR p.Arg58Pro](/variant/srr-p-arg58pro), [SRR p.Asp257Asn](/variant/srr-p-asp257asn), [SRR p.Asp258Gly](/variant/srr-p-asp258gly), [SRR p.Gln296Glu](/variant/srr-p-gln296glu), [SRR p.Gln296His](/variant/srr-p-gln296his), [SRR p.Glu304Gln](/variant/srr-p-glu304gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3449491). 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.*