Is ERCC1 p.Arg41Ter (c.121C>T) pathogenic?

ERCC1 p.Arg41Ter (c.121C>T) is classified Pathogenic in ERCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-06). Ultra-rare (popmax 0.0357%, mid); Associated with cerebrooculofacioskeletal syndrome 4.

What condition is associated with ERCC1 p.Arg41Ter (c.121C>T)?

ERCC1 p.Arg41Ter (c.121C>T) is associated with cerebrooculofacioskeletal syndrome 4 (ClinVar).

How common is ERCC1 p.Arg41Ter (c.121C>T) in the general population?

ERCC1 p.Arg41Ter (c.121C>T) is ultra-rare (popmax 0.0357%, mid) (gnomAD).

ERCC1 p.Arg41Ter

c.121C>T · rs867518898 · VCV1322828

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, mid)

Conditions

cerebrooculofacioskeletal syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 10
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.9	GERP 0.53, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% Middle Eastern · 2/5,600 alleles

Filtering AF 0.00626% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00258%

Overall 0.0007% 11/1,572,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0357%	2,800
European (non-Finnish)	0.000776%	128,925

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: ERCC1
Protein: p.Arg41Ter
Coding: c.121C>T
MANE Select: NM_001983
dbSNP: rs867518898
Type: single nucleotide variant
Location: chr19:45421378 (GRCh38)
Gene constraint: LOEUF 1.306 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 14 PDB

Full ERCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebrooculofacioskeletal syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC1 p.Arg156Gln Uncertain significance ★★ ⚠ same condition
ERCC1 p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ERCC1 p.Ser267Pro Uncertain significance ★★ ⚠ same condition
ERCC1 c.843+32G>A Benign/Likely benign ★★ same condition
POLR1G p.Thr282Ala Benign ★★ same condition
ERCC1 p.Glu62Ter Likely pathogenic ★ same condition
ERCC1 p.Phe231Leu Pathogenic ★ ⚠ same condition
ERCC1 c.843+32G>C 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/ercc1-p-arg41ter (accessed [today's date]).

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