Is ERCC2 p.Pro103Leu (c.308C>T) pathogenic?

ERCC2 p.Pro103Leu (c.308C>T) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). AlphaMissense: likely benign (0.0852); Ultra-rare (popmax 0.0108%, nfe); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Pro103Leu (c.308C>T)?

ERCC2 p.Pro103Leu (c.308C>T) is associated with xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Pro103Leu (c.308C>T) in the general population?

ERCC2 p.Pro103Leu (c.308C>T) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Pro103Leu (c.308C>T)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

ERCC2 p.Pro103Leu

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

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

c.308C>T · rs142462393 · VCV329528

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -3.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	14.97	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 0.0108% European (non-Finnish) · 127/1,180,008 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00863%

Overall 0.00818% 132/1,614,034 alleles · ultra-rare exomes 124/1,461,812 · genomes 8/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,291
Admixed American	0.00333%	29,991
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	74,940

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: ERCC2
Protein: p.Pro103Leu
Coding: c.308C>T
MANE Select: NM_000400
dbSNP: rs142462393
Type: single nucleotide variant
Location: chr19:45368682 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 103: the helicase atp-binding domain

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Pro103= Likely benign ★★ same residue
ERCC2 p.Pro103Arg Uncertain significance ★ ⚠ same residue
MAG p.Leu103Gln Uncertain significance ★ ⚠ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ 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/ercc2-p-pro103leu (accessed [today's date]).

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