Is AATF p.Pro553His (c.1658C>A) pathogenic?

AATF p.Pro553His (c.1658C>A) is classified Uncertain significance in AATF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely benign (0.064); Ultra-rare (popmax 0.0263%, sas).

How common is AATF p.Pro553His (c.1658C>A) in the general population?

AATF p.Pro553His (c.1658C>A) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about AATF p.Pro553His (c.1658C>A)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

AATF p.Pro553His

c.1658C>A · VCV3485063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.42	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 0.83	GERP 0.22
Regional constraint	o/e 0.93	unconstrained · MANE · 108 kb · p 0.074 · regional, not allelic
Overall
CADD	15.66	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 0.0263% South Asian · 24/91,094 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00186% 30/1,614,154 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,796
East Asian	0.0111%	8,980
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: AATF
Protein: p.Pro553His
Coding: c.1658C>A
MANE Select: NM_012138
Type: single nucleotide variant
Location: chr17:37056639 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.74 · 3 PDB

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

Similar variants

AATF p.Pro553Ser Uncertain significance ★ ⚠ same residue
AATF p.Ala198Pro Uncertain significance ★ ⚠ same type
AATF p.Ala198Thr Uncertain significance ★ ⚠ same type
AATF p.Ala226Thr Uncertain significance ★ ⚠ same type
AATF p.Ala247Val Uncertain significance ★ ⚠ same type
AATF p.Ala2Gly Uncertain significance ★ ⚠ same type
AATF p.Ala314Val Uncertain significance ★ ⚠ same type
AATF p.Ala377Pro 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/aatf-p-pro553his (accessed [today's date]).

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