Is ERCC6 p.Pro1095Ala (c.3283C>G) pathogenic?

ERCC6 p.Pro1095Ala (c.3283C>G) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-02). AlphaMissense: likely benign (0.0652); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ERCC6 p.Pro1095Ala (c.3283C>G)?

ERCC6 p.Pro1095Ala (c.3283C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6 p.Pro1095Ala (c.3283C>G) in the general population?

ERCC6 p.Pro1095Ala (c.3283C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC6 p.Pro1095Ala (c.3283C>G)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

ERCC6 p.Pro1095Ala

c.3283C>G · rs1311535007 · VCV1707166

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -5.38	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 0.62	GERP 1.1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	1.206	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 0.00223% East Asian · 1/44,862 alleles

Overall 0.000137% 2/1,461,688 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	8.47e-05%	1,179,974

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.Pro1095Ala
Coding: c.3283C>G
MANE Select: NM_000124
dbSNP: rs1311535007
Type: single nucleotide variant
Location: chr10:49470677 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 1095: a UniProt-annotated variant site (in); the 'disordered' 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 p.Pro1095Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC6 p.Pro1095Leu Likely benign ★ same residue
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

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-pro1095ala (accessed [today's date]).

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