Is ERCC4 p.Ser613Ter (c.1838C>G) pathogenic?

ERCC4 p.Ser613Ter (c.1838C>G) is classified Likely pathogenic in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-05). Very rare (popmax 0.000763%, nfe).

How common is ERCC4 p.Ser613Ter (c.1838C>G) in the general population?

ERCC4 p.Ser613Ter (c.1838C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

ERCC4 p.Ser613Ter

c.1838C>G · rs2543184108 · VCV1723058

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

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 9 of 11
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Pangolin	Δ0.31	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Overall
CADD	43.0	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 0.000763% European (non-Finnish) · 9/1,179,226 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000821% 12/1,460,974 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)grpmax	0.000763%	131,025

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ERCC4
Protein: p.Ser613Ter
Coding: c.1838C>G
MANE Select: NM_005236
dbSNP: rs2543184108
Type: single nucleotide variant
Location: chr16:13937792 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC4 c.1102+1G>T Likely pathogenic ★★ same type
ERCC4 c.793-2A>G Pathogenic ★★ same type
ERCC4 p.Arg20Ter Pathogenic ★★ same type
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Arg689Ser Likely pathogenic ★★ same type
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Cys236Arg Pathogenic/Likely pathogenic ★★ same type
ERCC4 p.Cys723Ter Pathogenic/Likely pathogenic ★★ 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/ercc4-p-ser613ter (accessed [today's date]).

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