Is ERCC6 p.Arg447Trp (c.1339C>T) pathogenic?

ERCC6 p.Arg447Trp (c.1339C>T) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1087); Ultra-rare (popmax 0.0484%, amr).

How common is ERCC6 p.Arg447Trp (c.1339C>T) in the general population?

ERCC6 p.Arg447Trp (c.1339C>T) is ultra-rare (popmax 0.0484%, amr) (gnomAD).

What do computational predictors say about ERCC6 p.Arg447Trp (c.1339C>T)?

AlphaMissense predicts likely benign (score 0.1087) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg447Trp

c.1339C>T · rs200818896 · VCV2198816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1087	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2	GERP 0.22, phastCons 0.014
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	23.6	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 0.0484% Admixed American · 29/59,976 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0139% 224/1,613,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0484%	2,068
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)	0.0145%	6,900
African / African-American	0.012%	8,316
East Asian	0.00446%	22,435

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.Arg447Trp
Coding: c.1339C>T
MANE Select: NM_000124
dbSNP: rs200818896
Type: single nucleotide variant
Location: chr10:49524091 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 447: 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

Similar variants

ERCC6 p.Arg447Gln Uncertain significance ★★ ⚠ same residue
ERCC6 c.1397+1G>C Likely pathogenic ★★ same type
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2169+1G>A Likely pathogenic ★★ same type
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2599-26A>G Pathogenic/Likely pathogenic ★★ same type

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-arg447trp (accessed [today's date]).

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