Is ERCC6 p.Ser46Phe (c.137C>T) pathogenic?

ERCC6 p.Ser46Phe (c.137C>T) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0253%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC6 p.Ser46Phe (c.137C>T)?

ERCC6 p.Ser46Phe (c.137C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6 p.Ser46Phe (c.137C>T) in the general population?

ERCC6 p.Ser46Phe (c.137C>T) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

What do computational predictors say about ERCC6 p.Ser46Phe (c.137C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

ERCC6 p.Ser46Phe

c.137C>T · rs570753448 · VCV3090116

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -7.90	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 0.44	GERP -2
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	1.536	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 0.0253% African / African-American · 19/75,046 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0018% 29/1,614,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,950
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Admixed American	0.00167%	60,024
South Asian	0.0011%	91,078
European (non-Finnish)	8.47e-05%	1,180,020

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.Ser46Phe
Coding: c.137C>T
MANE Select: NM_000124
dbSNP: rs570753448
Type: single nucleotide variant
Location: chr10:49532828 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 46: 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-ser46phe (accessed [today's date]).

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