Is ATAD5 p.Pro133Ser (c.397C>T) pathogenic?

ATAD5 p.Pro133Ser (c.397C>T) is classified Uncertain significance in ATAD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1112); Ultra-rare (popmax 0.0232%, afr).

How common is ATAD5 p.Pro133Ser (c.397C>T) in the general population?

ATAD5 p.Pro133Ser (c.397C>T) is ultra-rare (popmax 0.0232%, afr) (gnomAD).

What do computational predictors say about ATAD5 p.Pro133Ser (c.397C>T)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

ATAD5 p.Pro133Ser

c.397C>T · VCV3959406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.16	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 0.86	GERP -0.039, phastCons 0.28
Regional constraint	o/e 0.98	unconstrained · MANE · 3,612 bp · p 0.54 · regional, not allelic
Overall
CADD	6.756	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 0.0232% African / African-American · 17/73,160 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0012% 19/1,586,330 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0232%	4,304
Remaining individualsnot grpmax-eligible	0.00326%	30,678

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: ATAD5
Protein: p.Pro133Ser
Coding: c.397C>T
MANE Select: NM_024857
Type: single nucleotide variant
Location: chr17:30834478 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.76 · 4 PDB

Full ATAD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATAD5 c.4013-8G>A Benign ★★ same type
ATAD5 p.Asp826= Likely benign ★★ same type
ATAD5 p.Ala1326Thr Uncertain significance ★ ⚠ same type
ATAD5 p.Ala1459Thr Uncertain significance ★ ⚠ same type
ATAD5 p.Ala1539Pro Uncertain significance ★ ⚠ same type
ATAD5 p.Ala1711Val Uncertain significance ★ ⚠ same type
ATAD5 p.Ala326Val Uncertain significance ★ ⚠ same type
ATAD5 p.Ala414Thr 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/atad5-p-pro133ser (accessed [today's date]).

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