Is ERCC3 p.Ser221Phe (c.662C>T) pathogenic?

ERCC3 p.Ser221Phe (c.662C>T) is classified Uncertain significance in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely benign (0.1614); Very rare (popmax 0.00134%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC3 p.Ser221Phe (c.662C>T)?

ERCC3 p.Ser221Phe (c.662C>T) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Ser221Phe (c.662C>T) in the general population?

ERCC3 p.Ser221Phe (c.662C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ERCC3 p.Ser221Phe (c.662C>T)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

ERCC3 p.Ser221Phe

c.662C>T · rs1167535533 · VCV1692170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -8.13	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	24.6	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 0.00134% African / African-American · 1/74,874 alleles

Overall 0.00131% 2/152,198 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,874
European (non-Finnish)	8.47e-05%	1,180,036

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: ERCC3
Protein: p.Ser221Phe
Coding: c.662C>T
MANE Select: NM_000122
dbSNP: rs1167535533
Type: single nucleotide variant
Location: chr2:127289497 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 221: the 'disordered' region

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter Pathogenic ★★ same condition
ERCC3 p.Glu434Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Glu105Gly Uncertain significance ★★ ⚠ same condition
ERCC3 p.Glu48Asp Uncertain significance ★★ ⚠ same condition
ERCC3 p.Glu48Gly 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/ercc3-p-ser221phe (accessed [today's date]).

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