Is ATG4D p.Pro191Ser (c.571C>T) pathogenic?

ATG4D p.Pro191Ser (c.571C>T) is classified Uncertain significance in ATG4D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0749); Ultra-rare (popmax 0.0454%, afr).

How common is ATG4D p.Pro191Ser (c.571C>T) in the general population?

ATG4D p.Pro191Ser (c.571C>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

What do computational predictors say about ATG4D p.Pro191Ser (c.571C>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

ATG4D p.Pro191Ser

c.571C>T · VCV4643913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.38	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 1.7	GERP 1.2, phastCons 0.004
Regional constraint	o/e 0.98	unconstrained · MANE · 8,973 bp · p 0.57 · regional, not allelic
Overall
CADD	18.53	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 0.0454% African / African-American · 34/74,922 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.0023% 37/1,612,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,204
Remaining individualsnot grpmax-eligible	0.00481%	20,794

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.Pro191Ser
Coding: c.571C>T
MANE Select: NM_032885
Type: single nucleotide variant
Location: chr19:10546916 (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.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-pro191ser (accessed [today's date]).

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