Is ERCC6 p.Arg293Ser (c.879A>T) pathogenic?

ERCC6 p.Arg293Ser (c.879A>T) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.3488); Ultra-rare (popmax 0.0703%, sas); Associated with Inborn genetic diseases.

What condition is associated with ERCC6 p.Arg293Ser (c.879A>T)?

ERCC6 p.Arg293Ser (c.879A>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6 p.Arg293Ser (c.879A>T) in the general population?

ERCC6 p.Arg293Ser (c.879A>T) is ultra-rare (popmax 0.0703%, sas) (gnomAD).

What do computational predictors say about ERCC6 p.Arg293Ser (c.879A>T)?

AlphaMissense predicts ambiguous (score 0.3488) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg293Ser

c.879A>T · rs563356062 · VCV1049147

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3488 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3488	ambiguous
REVEL	0.085	moderately benign-leaning
SaProt	LLR -5.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -0.41, phastCons 0.64
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	17.07	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% South Asian · 64/91,090 alleles

Filtering AF 0.0564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00427% 69/1,614,268 alleles · ultra-rare exomes 67/1,461,886 · genomes 2/152,382 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0703%	1,423
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.000169%	590,023

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: ERCC6
Protein: p.Arg293Ser
Coding: c.879A>T
MANE Select: NM_000124
dbSNP: rs563356062
Type: single nucleotide variant
Location: chr10:49524551 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 293: the 'disordered' region; the 'n-terminal domain; essential for its chromatin remodeling activity' region

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC6 c.1397+1G>C Likely pathogenic ★★ same condition
ERCC6 p.Arg176Ter Pathogenic ★★ same condition
ERCC6 p.Arg612Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC6 p.Arg857Ter Pathogenic ★★ same condition
ERCC6 p.Gln723Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC6 p.Ser687Leu Pathogenic ★★ same condition
ERCC6 p.Ala1075Thr Uncertain significance ★★ ⚠ same condition
ERCC6 p.Ala1167Asp 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/ercc6-p-arg293ser (accessed [today's date]).

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