# NM_004083.6(DDIT3):c.29T>C (p.Phe10Ser)

https://sugi.bio/variant/ddit3-p-phe10ser

## Summary

**DDIT3 p.Phe10Ser (c.29T>C)** is classified **Uncertain significance** in DDIT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1266); Very rare (popmax 0.0022%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the DDIT3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DDIT3](https://sugi.bio/atlas/gene/DDIT3/) |
| Protein change (HGVS p.) | p.Phe10Ser |
| Coding change (HGVS c.) | c.29T>C |
| MANE Select transcript | [NM_004083](https://www.ncbi.nlm.nih.gov/nuccore/NM_004083) |
| Variant type | single nucleotide variant |
| Location | chr12:57517378-57517378 (GRCh38) |
| ClinVar | [VCV4238420](https://www.ncbi.nlm.nih.gov/clinvar/variation/4238420/) |

**All HGVS expressions:** `NC_000012.11:g.57911161A>G`, `NC_000012.12:g.57517378A>G`, `NG_027674.1:g.8140T>C`, `NG_034077.1:g.34426A>G`, `NM_001195053.1:c.98T>C`, `NM_001195054.1:c.98T>C`, `NM_001195055.1:c.98T>C`, `NM_001195056.1:c.98T>C`, `NM_001195057.1:c.29T>C`, `NM_001413641.1:c.29T>C`, `NM_001413642.1:c.29T>C`, `NM_004083.6:c.29T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1266)
- REVEL 0.128 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.778 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.862, GERP 2.35, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.7**. 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 1.07** across the covering region of the MANE Select transcript (57,516,812–57,517,406), spanning 594 bp. Chi-square p 0.35. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.25 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000159% · 2/91,082 in the highest group · 9/1,611,824 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,541 |
| European (non-Finnish) | 0.000593% | 168,573 |

*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}

**DDIT3** population constraint: LOEUF 1.188, pLI 0.00014889, missense-Z -0.17088. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **10** lies in the 'n-terminal' region; the 'interaction with trib3' region.

AlphaFold model confidence (whole protein): pLDDT 84.76, 17% of residues very-high.

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

*Describes the biological roles of DDIT3 (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:** DDIT3's established molecular role includes transcription cis-regulatory region binding. p.Phe10Ser falls in the n-terminal region.


### Pathways affected {#pathways}

DDIT3 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ATF4 activates genes in response to endoplasmic reticulum  stress](https://reactome.org/content/detail/R-HSA-380994) | electronic |
| [ATF6 (ATF6-alpha) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381183) | electronic |
| [FOXO-mediated transcription of cell death genes](https://reactome.org/content/detail/R-HSA-9614657) | electronic |
| [Response of EIF2AK1 (HRI) to heme deficiency](https://reactome.org/content/detail/R-HSA-9648895) | electronic |
| [Response of EIF2AK4 (GCN2) to amino acid deficiency](https://reactome.org/content/detail/R-HSA-9633012) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA binding, DNA-binding transcription factor activity, transcription corepressor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, response to unfolded protein, negative regulation of type II interferon production, negative regulation of interleukin-17 production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-26 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DDIT3 variant pages (same residue, condition, or type): [DDIT3 c.-23T>C](/variant/ddit3-c-minus-23t-c), [DDIT3 c.-32-25C>G](/variant/ddit3-c-minus-32-minus-25c-g), [DDIT3 p.Glu146Lys](/variant/ddit3-p-glu146lys), [DDIT3 c.-15G>A](/variant/ddit3-c-minus-15g-a), [DDIT3 c.-32-6C>G](/variant/ddit3-c-minus-32-minus-6c-g), [DDIT3 c.*17G>A](/variant/ddit3-c-star-17g-a), [DDIT3 p.Arg103Lys](/variant/ddit3-p-arg103lys), [DDIT3 p.Arg105Gln](/variant/ddit3-p-arg105gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4238420). 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.*