Is ERCC6 p.Pro1095Arg (c.3284C>G) pathogenic?

ERCC6 p.Pro1095Arg (c.3284C>G) is classified Conflicting classifications of pathogenicity in ERCC6 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0772); Low-frequency (popmax 4.37%, afr); Associated with de Sanctis-Cacchione syndrome.

What condition is associated with ERCC6 p.Pro1095Arg (c.3284C>G)?

ERCC6 p.Pro1095Arg (c.3284C>G) is associated with de Sanctis-Cacchione syndrome, cerebrooculofacioskeletal syndrome 1, age related macular degeneration 5 (ClinVar).

How common is ERCC6 p.Pro1095Arg (c.3284C>G) in the general population?

ERCC6 p.Pro1095Arg (c.3284C>G) is low-frequency (popmax 4.37%, afr) (gnomAD).

What do computational predictors say about ERCC6 p.Pro1095Arg (c.3284C>G)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

ERCC6 p.Pro1095Arg

c.3284C>G · rs4253208 · VCV1707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.37%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

de Sanctis-Cacchione syndrome

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -6.21	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 1.2	GERP 0.16, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	12.07	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 4.37% African / African-American · 3,278/75,014 alleles

Filtering AF 4.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.19%

Overall 0.223% 3,607/1,613,920 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.37%	23
Remaining individualsnot grpmax-eligible	0.256%	391
Admixed American	0.218%	458
Middle Eastern	0.0825%	1,212
South Asian	0.00988%	10,118
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.00195%	51,304

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.Pro1095Arg
Coding: c.3284C>G
MANE Select: NM_000124
dbSNP: rs4253208
Type: single nucleotide variant
Location: chr10:49470676 (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

de Sanctis-Cacchione syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebrooculofacioskeletal syndrome 1 age related macular degeneration 5 Cockayne syndrome type 2

Similar variants

ERCC6 p.Pro1095Ala Uncertain significance ★★ ⚠ same residue
ERCC6 p.Pro1095Leu Likely benign ★ 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

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-pro1095arg (accessed [today's date]).

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