Is ERCC5 p.Pro1122Ser (c.3364C>T) pathogenic?

ERCC5 p.Pro1122Ser (c.3364C>T) is classified Uncertain significance in ERCC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-20). AlphaMissense: likely benign (0.0705); Very rare (popmax 0.00891%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ERCC5 p.Pro1122Ser (c.3364C>T)?

ERCC5 p.Pro1122Ser (c.3364C>T) is associated with hereditary neoplastic syndrome, xeroderma pigmentosum group G, cerebrooculofacioskeletal syndrome 3 (ClinVar).

How common is ERCC5 p.Pro1122Ser (c.3364C>T) in the general population?

ERCC5 p.Pro1122Ser (c.3364C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ERCC5 p.Pro1122Ser (c.3364C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

ERCC5 p.Pro1122Ser

c.3364C>T · rs765714657 · VCV1692192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.003	strongly benign-leaning
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.9	GERP -4.2
Regional constraint	o/e 1.05	unconstrained · MANE · 7,648 bp · p 0.37 · regional, not allelic
Overall
CADD	0.005	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 0.00891% East Asian · 4/44,896 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,613,966 alleles · very rare exomes 3/1,461,870 · genomes 1/152,096 · joint denominator

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: ERCC5
Protein: p.Pro1122Ser
Coding: c.3364C>T
MANE Select: NM_000123
dbSNP: rs765714657
Type: single nucleotide variant
Location: chr13:102875706 (GRCh38)

Full ERCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group G cerebrooculofacioskeletal syndrome 3

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/ercc5-p-pro1122ser (accessed [today's date]).

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