Is XRCC4 p.Phe331Ser (c.992T>C) pathogenic?

XRCC4 p.Phe331Ser (c.992T>C) is classified Uncertain significance in XRCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: ambiguous (0.5343); Absent from gnomAD v4.1; Associated with short stature, microcephaly, and endocrine dysfunction.

What condition is associated with XRCC4 p.Phe331Ser (c.992T>C)?

XRCC4 p.Phe331Ser (c.992T>C) is associated with short stature, microcephaly, and endocrine dysfunction (ClinVar).

How common is XRCC4 p.Phe331Ser (c.992T>C) in the general population?

XRCC4 p.Phe331Ser (c.992T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about XRCC4 p.Phe331Ser (c.992T>C)?

AlphaMissense predicts ambiguous (score 0.5343) — an in-silico prediction, not a clinical call.

XRCC4 p.Phe331Ser

c.992T>C · VCV3592814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5343 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

short stature, microcephaly, and endocrine dysfunction

Computational evidence

Protein change
AlphaMissense	0.5343	ambiguous
REVEL	0.38	indeterminate
SaProt	LLR -8.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 248 kb · p 0.17 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F333S vs ClinVar F331S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: XRCC4
Protein: p.Phe331Ser
Coding: c.992T>C
MANE Select: NM_003401
Type: single nucleotide variant
Location: chr5:83353229 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.50 · 36 PDB
Residue 333 UniProt numbering: a UniProt-annotated variant site (in ssmed); the 'disordered' region

Full XRCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short stature, microcephaly, and endocrine dysfunction — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XRCC4 c.140-2A>G Likely pathogenic ★★ same condition
XRCC4 p.Arg161Ter Pathogenic/Likely pathogenic ★★ same condition
XRCC4 p.Arg205Ter Pathogenic/Likely pathogenic ★★ same condition
XRCC4 p.Arg225Ter Pathogenic ★★ same condition
XRCC4 p.Lys210Ter Likely pathogenic ★★ same condition
XRCC4 p.Trp43Arg Pathogenic/Likely pathogenic ★★ same condition
XRCC4 p.Ala56Thr Uncertain significance ★★ ⚠ same condition
XRCC4 p.Ala78Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/xrcc4-p-phe331ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown