Is ERCC4 p.Asp541Val (c.1622A>T) pathogenic?

ERCC4 p.Asp541Val (c.1622A>T) is classified Uncertain significance in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). AlphaMissense: likely benign (0.1538); Very rare (popmax 6.84e-05%).

How common is ERCC4 p.Asp541Val (c.1622A>T) in the general population?

ERCC4 p.Asp541Val (c.1622A>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ERCC4 p.Asp541Val (c.1622A>T)?

AlphaMissense predicts likely benign (score 0.1538) — an in-silico prediction, not a clinical call.

ERCC4 p.Asp541Val

c.1622A>T · VCV3766877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1538	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,888 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: ERCC4
Protein: p.Asp541Val
Coding: c.1622A>T
MANE Select: NM_005236
Type: single nucleotide variant
Location: chr16:13935554 (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 p.Asp541Asn Uncertain significance ★ ⚠ same residue
ERCC4 p.Asp541Gly Uncertain significance ★ ⚠ same residue
ERCC4 p.Asp541= Likely benign ★ same residue
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

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-asp541val (accessed [today's date]).

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