Is ERCC3 p.Glu48Asp (c.144G>C) pathogenic?

ERCC3 p.Glu48Asp (c.144G>C) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-11-01). AlphaMissense: likely benign (0.0597); Rare (popmax 0.142%, amr); Associated with xeroderma pigmentosum group B.

What condition is associated with ERCC3 p.Glu48Asp (c.144G>C)?

ERCC3 p.Glu48Asp (c.144G>C) is associated with xeroderma pigmentosum group B, trichothiodystrophy 2, photosensitive, xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Glu48Asp (c.144G>C) in the general population?

ERCC3 p.Glu48Asp (c.144G>C) is rare (popmax 0.142%, amr) (gnomAD).

What do computational predictors say about ERCC3 p.Glu48Asp (c.144G>C)?

AlphaMissense predicts likely benign (score 0.0597) — an in-silico prediction, not a clinical call.

ERCC3 p.Glu48Asp

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

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

c.144G>C · rs149309991 · VCV893901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0597 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.142%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group B

Computational evidence

Protein change
AlphaMissense	0.0597	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -5.58	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 0.21	GERP -1.7, phastCons 0.95
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	16.43	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 0.142% Admixed American · 85/60,034 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.026% 419/1,614,214 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.142%	706
Remaining individualsnot grpmax-eligible	0.0272%	3,677
European (non-Finnish)	0.0267%	3,746
Finnishnot grpmax-eligible	0.00312%	32,017

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.Glu48Asp
Coding: c.144G>C
MANE Select: NM_000122
dbSNP: rs149309991
Type: single nucleotide variant
Location: chr2:127293603 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 48: the 'disordered' region

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

Disease context

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

Also linked: trichothiodystrophy 2, photosensitive xeroderma pigmentosum

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC3 p.Glu48Gly Uncertain significance ★★ ⚠ same residue
ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
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.Arg425Ter Pathogenic ★★ same condition
ERCC3 p.Arg452Ter 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/ercc3-p-glu48asp (accessed [today's date]).

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