Is ERCC6 p.Ser1068Thr (c.3202T>A) pathogenic?

ERCC6 p.Ser1068Thr (c.3202T>A) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0691); Very rare (popmax 0.000932%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC6 p.Ser1068Thr (c.3202T>A)?

ERCC6 p.Ser1068Thr (c.3202T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC6 p.Ser1068Thr (c.3202T>A) in the general population?

ERCC6 p.Ser1068Thr (c.3202T>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about ERCC6 p.Ser1068Thr (c.3202T>A)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

ERCC6 p.Ser1068Thr

c.3202T>A · rs896621508 · VCV2318009

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.98	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 0.32	GERP -1.9
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	7.269	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 0.000932% European (non-Finnish) · 11/1,180,044 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,614,018 alleles · very rare

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.Ser1068Thr
Coding: c.3202T>A
MANE Select: NM_000124
dbSNP: rs896621508
Type: single nucleotide variant
Location: chr10:49470758 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 1068: 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.Ser1068= 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
ERCC6 p.Ala1075Thr 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-ser1068thr (accessed [today's date]).

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