Is ERCC4 p.Tyr577Ter (c.1730dup) pathogenic?

ERCC4 p.Tyr577Ter (c.1730dup) is classified Pathogenic in ERCC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-01-04). Very rare (popmax 0.00167%, amr); Associated with spastic ataxia.

What condition is associated with ERCC4 p.Tyr577Ter (c.1730dup)?

ERCC4 p.Tyr577Ter (c.1730dup) is associated with spastic ataxia, xeroderma pigmentosum group F, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Tyr577Ter (c.1730dup) in the general population?

ERCC4 p.Tyr577Ter (c.1730dup) is very rare (popmax 0.00167%, amr) (gnomAD).

ERCC4 p.Tyr577Ter

c.1730dup · rs397509404 · VCV55828

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

spastic ataxia

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 8 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
South Asian	0.0011%	91,072
European (non-Finnish)	0.000169%	590,012

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.Tyr577Ter
Coding: c.1730dup
MANE Select: NM_005236
dbSNP: rs397509404
Type: Duplication
Location: chr16:13935661 (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

Disease context

spastic ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group F Fanconi anemia complementation group Q Cockayne syndrome xeroderma pigmentosum, type F/Cockayne syndrome

Similar variants

ERCC4 p.Arg314fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Gln473fs Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Ile553fs Likely pathogenic ★ same condition
ERCC4 p.Ile800fs Likely pathogenic ★ same condition
ERCC4 p.Met222fs Pathogenic ★ same condition
ERCC4 p.Met748fs Pathogenic ★ same condition
ERCC4 c.1892_1904+41dup Uncertain significance ★ same condition
ERCC4 c.1102+36dup Likely benign ★ 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/ercc4-p-tyr577ter (accessed [today's date]).

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