Is ERCC3 p.Ser614Ter (c.1841C>A) pathogenic?

ERCC3 p.Ser614Ter (c.1841C>A) is classified Pathogenic in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). Very rare (popmax 0.00133%, afr); Associated with xeroderma pigmentosum.

What condition is associated with ERCC3 p.Ser614Ter (c.1841C>A)?

ERCC3 p.Ser614Ter (c.1841C>A) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Ser614Ter (c.1841C>A) in the general population?

ERCC3 p.Ser614Ter (c.1841C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

ERCC3 p.Ser614Ter

c.1841C>A · VCV3630007

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.27	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Overall
CADD	48.0	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 0.00133% African / African-American · 1/74,928 alleles

Overall 6.84e-05% 1/1,461,292 alleles · very rare

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.Ser614Ter
Coding: c.1841C>A
MANE Select: NM_000122
Type: single nucleotide variant
Location: chr2:127271440 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 614: the helicase c-terminal domain; a turn

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 p.Ser614= Likely benign ★★ same residue
ERCC3 p.Ser614Leu Uncertain significance ★ ⚠ same residue
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

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-ser614ter (accessed [today's date]).

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