Is ERCC1 p.Leu69= (c.205C>T) pathogenic?

ERCC1 p.Leu69= (c.205C>T) is classified Likely benign in ERCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-26). Ultra-rare (popmax 0.066%, mid).

How common is ERCC1 p.Leu69= (c.205C>T) in the general population?

ERCC1 p.Leu69= (c.205C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

ERCC1 p.Leu69=

c.205C>T · rs139307454 · VCV1990232

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -3, phastCons 0.012
Overall
CADD	0.588	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,058 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00211% 34/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,514
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00195%	51,307
South Asian	0.0011%	91,086

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.Leu69=
Coding: c.205C>T
MANE Select: NM_001983
dbSNP: rs139307454
Type: single nucleotide variant
Location: chr19:45421294 (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

Similar variants

POLR1G p.Val69Ile Uncertain significance ★ ⚠ same residue
ERCC1 c.526-1G>A Likely pathogenic ★★ same type
ERCC1 p.Arg41Ter Pathogenic ★★ same type
ERCC1 c.843+52A>G Uncertain significance ★★ same type
ERCC1 p.Ala265Thr Uncertain significance ★★ ⚠ same type
ERCC1 p.Arg156Gln Uncertain significance ★★ ⚠ same type
ERCC1 p.Arg207Trp Uncertain significance ★★ ⚠ same type
ERCC1 p.Asn110Ser Uncertain significance ★★ ⚠ same type

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-leu69 (accessed [today's date]).

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