Is ERCC4 p.Ala7Thr (c.19G>A) pathogenic?

ERCC4 p.Ala7Thr (c.19G>A) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.0329%, sas); Associated with Cockayne syndrome.

What condition is associated with ERCC4 p.Ala7Thr (c.19G>A)?

ERCC4 p.Ala7Thr (c.19G>A) is associated with Cockayne syndrome, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Ala7Thr (c.19G>A) in the general population?

ERCC4 p.Ala7Thr (c.19G>A) is ultra-rare (popmax 0.0329%, sas) (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.Ala7Thr (c.19G>A)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

ERCC4 p.Ala7Thr

c.19G>A · rs771117594 · VCV568412

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cockayne syndrome

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	18.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0329% South Asian · 30/91,058 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00224% 36/1,605,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,035
Remaining individualsnot grpmax-eligible	0.00962%	10,400

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.Ala7Thr
Coding: c.19G>A
MANE Select: NM_005236
dbSNP: rs771117594
Type: single nucleotide variant
Location: chr16:13920184 (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 7: 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 p.Ala7Val Uncertain significance ★ ⚠ same residue
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

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-ala7thr (accessed [today's date]).

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