Is ATG4D p.Arg102Pro (c.305G>C) pathogenic?

ATG4D p.Arg102Pro (c.305G>C) is classified Uncertain significance in ATG4D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely benign (0.2332); Very rare (popmax 0.00446%, eas).

How common is ATG4D p.Arg102Pro (c.305G>C) in the general population?

ATG4D p.Arg102Pro (c.305G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ATG4D p.Arg102Pro (c.305G>C)?

AlphaMissense predicts likely benign (score 0.2332) — an in-silico prediction, not a clinical call.

ATG4D p.Arg102Pro

c.305G>C · VCV3321340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2332	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -11.86	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,973 bp · p 0.57 · regional, not allelic
Overall
CADD	21.4	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 0.00446% East Asian · 2/44,856 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000137% 2/1,459,234 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: ATG4D
Protein: p.Arg102Pro
Coding: c.305G>C
MANE Select: NM_032885
Type: single nucleotide variant
Location: chr19:10544852 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.22
Residue 102: the 'cryptic mitochondrial signal peptide' 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.Arg111Cys Uncertain significance ★ ⚠ same type
ATG4D p.Arg111Ser Uncertain significance ★ ⚠ same type
ATG4D p.Arg12Trp 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-arg102pro (accessed [today's date]).

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