Is ERCC6 p.Met752Val (c.2254A>G) pathogenic?

ERCC6 p.Met752Val (c.2254A>G) is classified Pathogenic in ERCC6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-09-01). AlphaMissense: likely benign (0.174); Absent from gnomAD v4.1; Associated with cerebrooculofacioskeletal syndrome 1.

What condition is associated with ERCC6 p.Met752Val (c.2254A>G)?

ERCC6 p.Met752Val (c.2254A>G) is associated with cerebrooculofacioskeletal syndrome 1 (ClinVar).

How common is ERCC6 p.Met752Val (c.2254A>G) in the general population?

ERCC6 p.Met752Val (c.2254A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERCC6 p.Met752Val (c.2254A>G)?

AlphaMissense predicts likely benign (score 0.174) — an in-silico prediction, not a clinical call.

ERCC6 p.Met752Val

c.2254A>G · rs1590413260 · VCV1713

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.174 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cerebrooculofacioskeletal syndrome 1

Computational evidence

Protein change
AlphaMissense	0.174	likely benign ⚠ discordant with ClinVar
REVEL	0.3	indeterminate
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.99	donor gain, 1 bp away · masked 0 · deltas
Pangolin	Δ0.87	gain · loss 0.80 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	32.0	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

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: ERCC6
Protein: p.Met752Val
Coding: c.2254A>G
MANE Select: NM_000124
dbSNP: rs1590413260
Type: single nucleotide variant
Location: chr10:49478386 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 752: a turn

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

Disease context

cerebrooculofacioskeletal syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC6 p.Gln752Glu Uncertain significance ★ ⚠ same residue
ERCC6 c.1397+1G>C Likely pathogenic ★★ same condition
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2169+1G>A Likely pathogenic ★★ same condition
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC6 c.2599-26A>G 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/ercc6-p-met752val (accessed [today's date]).

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