Is ERCC4 p.Asp330Ala (c.989A>C) pathogenic?

ERCC4 p.Asp330Ala (c.989A>C) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6327); Very rare (popmax 0.00187%, nfe); Associated with Cockayne syndrome.

What condition is associated with ERCC4 p.Asp330Ala (c.989A>C)?

ERCC4 p.Asp330Ala (c.989A>C) is associated with Cockayne syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Asp330Ala (c.989A>C) in the general population?

ERCC4 p.Asp330Ala (c.989A>C) is very rare (popmax 0.00187%, nfe) (gnomAD).

How is Cockayne syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ERCC4 p.Asp330Ala (c.989A>C)?

AlphaMissense predicts likely pathogenic (score 0.6327) — an in-silico prediction, not a clinical call.

ERCC4 p.Asp330Ala

c.989A>C · rs777183693 · VCV1398105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cockayne syndrome

Computational evidence

Protein change
AlphaMissense	0.6327	likely pathogenic
REVEL	0.771	pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% European (non-Finnish) · 22/1,179,620 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,613,466 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,824
Finnishnot grpmax-eligible	0.00469%	21,321
European (non-Finnish)grpmax	0.00187%	53,619

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERCC4
Protein: p.Asp330Ala
Coding: c.989A>C
MANE Select: NM_005236
dbSNP: rs777183693
Type: single nucleotide variant
Location: chr16:13932172 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 330: the 'helicase-like' region

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cockayne syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group F Fanconi anemia complementation group Q

For Cockayne syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Arg20Ter Pathogenic ★★ same condition
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely pathogenic ★★ same condition
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys236Arg Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys723Ter Pathogenic/Likely pathogenic ★★ 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/ercc4-p-asp330ala (accessed [today's date]).

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