Is ERCC8 p.Thr48Ser (c.143C>G) pathogenic?

ERCC8 p.Thr48Ser (c.143C>G) is classified Uncertain significance in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC8 p.Thr48Ser (c.143C>G)?

ERCC8 p.Thr48Ser (c.143C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC8 p.Thr48Ser (c.143C>G) in the general population?

ERCC8 p.Thr48Ser (c.143C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ERCC8 p.Thr48Ser (c.143C>G)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

ERCC8 p.Thr48Ser

c.143C>G · VCV4618791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -4.64	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 6.4	GERP 0.84, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	16.4	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 0.00267% African / African-American · 2/74,810 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,280 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: ERCC8
Protein: p.Thr48Ser
Coding: c.143C>G
MANE Select: NM_000082
Type: single nucleotide variant
Location: chr5:60928894 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 48: a β-strand

Full ERCC8 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

ERCC8 p.Arg270Ser Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp136Gly Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp373Tyr Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp72His Uncertain significance ★★ ⚠ same condition
ERCC8 p.Gln169His Uncertain significance ★★ ⚠ same condition
ERCC8 p.Glu325Lys Uncertain significance ★★ ⚠ same condition
ERCC8 p.Gly91Arg Uncertain significance ★★ ⚠ same condition
ERCC8 p.Ile189Val 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/ercc8-p-thr48ser (accessed [today's date]).

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