Is ATG4D p.Arg231Trp (c.691C>T) pathogenic?

ATG4D p.Arg231Trp (c.691C>T) is classified Uncertain significance in ATG4D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: likely benign (0.1321); Very rare (popmax 0.0012%, nfe).

How common is ATG4D p.Arg231Trp (c.691C>T) in the general population?

ATG4D p.Arg231Trp (c.691C>T) is very rare (popmax 0.0012%, nfe) (gnomAD).

What do computational predictors say about ATG4D p.Arg231Trp (c.691C>T)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

ATG4D p.Arg231Trp

c.691C>T · rs776338785 · VCV2622287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0012%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -13.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,973 bp · p 0.57 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0012% European (non-Finnish) · 14/1,167,018 alleles

Filtering AF 0.000696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000545%

Overall 0.000946% 15/1,585,182 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0012%	83,358
South Asian	0.00114%	88,054

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: ATG4D
Protein: p.Arg231Trp
Coding: c.691C>T
MANE Select: NM_032885
dbSNP: rs776338785
Type: single nucleotide variant
Location: chr19:10547036 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.22

Full ATG4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATG4D p.Arg231Gln Uncertain significance ★ ⚠ same residue
ATG4D p.Ala259= Benign/Likely benign ★★ same type
ATG4D p.Pro305= Benign ★★ same type
ATG4D p.Ala421Thr Uncertain significance ★ ⚠ same type
ATG4D p.Ala448Pro Uncertain significance ★ ⚠ same type
ATG4D p.Ala448Thr Uncertain significance ★ ⚠ same type
ATG4D p.Arg102Pro Uncertain significance ★ ⚠ same type
ATG4D p.Arg111Cys 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/atg4d-p-arg231trp (accessed [today's date]).

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