Is ATG4D p.Arg12Trp (c.34C>T) pathogenic?

ATG4D p.Arg12Trp (c.34C>T) is classified Uncertain significance in ATG4D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.1978); Very rare (popmax 0.0076%, nfe).

How common is ATG4D p.Arg12Trp (c.34C>T) in the general population?

ATG4D p.Arg12Trp (c.34C>T) is very rare (popmax 0.0076%, nfe) (gnomAD).

What do computational predictors say about ATG4D p.Arg12Trp (c.34C>T)?

AlphaMissense predicts likely benign (score 0.1978) — an in-silico prediction, not a clinical call.

ATG4D p.Arg12Trp

c.34C>T · rs1000543180 · VCV2206922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0076%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1978	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -7.46	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 0.64	GERP -1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,973 bp · p 0.57 · regional, not allelic
Overall
CADD	20.8	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 0.0076% European (non-Finnish) · 75/986,424 alleles

Filtering AF 0.00621% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00566%

Overall 0.00636% 79/1,243,104 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0076%	13,152
South Asian	0.00411%	24,312
African / African-American	0.00311%	32,112
Remaining individualsnot grpmax-eligible	0.00219%	45,656

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.Arg12Trp
Coding: c.34C>T
MANE Select: NM_032885
dbSNP: rs1000543180
Type: single nucleotide variant
Location: chr19:10544124 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.22
Residue 12: the 'disordered' region

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

Similar variants

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
ATG4D p.Arg111Ser 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-arg12trp (accessed [today's date]).

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