Is ERCC8 p.Arg17Ser (c.49C>A) pathogenic?

ERCC8 p.Arg17Ser (c.49C>A) is classified Uncertain significance in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: ambiguous (0.442); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ERCC8 p.Arg17Ser (c.49C>A)?

ERCC8 p.Arg17Ser (c.49C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC8 p.Arg17Ser (c.49C>A) in the general population?

ERCC8 p.Arg17Ser (c.49C>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about ERCC8 p.Arg17Ser (c.49C>A)?

AlphaMissense predicts ambiguous (score 0.442) — an in-silico prediction, not a clinical call.

ERCC8 p.Arg17Ser

c.49C>A · rs1452939769 · VCV2220537

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.442 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.442	ambiguous
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	19.76	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 0.0167% Admixed American · 10/60,004 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000682% 11/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
European (non-Finnish)	8.47e-05%	1,179,990

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.Arg17Ser
Coding: c.49C>A
MANE Select: NM_000082
dbSNP: rs1452939769
Type: single nucleotide variant
Location: chr5:60944960 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 17: an α-helix

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.Arg17Pro Uncertain significance ★ ⚠ same residue
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

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-arg17ser (accessed [today's date]).

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