Is ATG4D p.Pro176Ser (c.526C>T) pathogenic?

ATG4D p.Pro176Ser (c.526C>T) is classified Uncertain significance in ATG4D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-07). AlphaMissense: likely benign (0.0673); Rare (popmax 0.13%, afr).

How common is ATG4D p.Pro176Ser (c.526C>T) in the general population?

ATG4D p.Pro176Ser (c.526C>T) is rare (popmax 0.13%, afr) (gnomAD).

What do computational predictors say about ATG4D p.Pro176Ser (c.526C>T)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

ATG4D p.Pro176Ser

c.526C>T · rs142336391 · VCV2372538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP 0.23
Regional constraint	o/e 0.98	unconstrained · MANE · 8,973 bp · p 0.57 · regional, not allelic
Overall
CADD	7.744	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 0.13% African / African-American · 97/74,874 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00736% 118/1,603,554 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.13%	772
Middle Eastern	0.0203%	4,922
Admixed American	0.0151%	6,613
Remaining individualsnot grpmax-eligible	0.00646%	15,475
South Asian	0.0011%	90,508
European (non-Finnish)	0.000511%	195,679

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.Pro176Ser
Coding: c.526C>T
MANE Select: NM_032885
dbSNP: rs142336391
Type: single nucleotide variant
Location: chr19:10546871 (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.Pro176Leu 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-pro176ser (accessed [today's date]).

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