Is ANKRD65 p.Arg91Pro (c.272G>C) pathogenic?

ANKRD65 p.Arg91Pro (c.272G>C) is classified Uncertain significance in ANKRD65 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.5732); Rare (popmax 0.121%, afr).

How common is ANKRD65 p.Arg91Pro (c.272G>C) in the general population?

ANKRD65 p.Arg91Pro (c.272G>C) is rare (popmax 0.121%, afr) (gnomAD).

What do computational predictors say about ANKRD65 p.Arg91Pro (c.272G>C)?

AlphaMissense predicts likely pathogenic (score 0.5732) — an in-silico prediction, not a clinical call.

ANKRD65 p.Arg91Pro

c.272G>C · VCV3874005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5732 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.121%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5732	likely pathogenic
REVEL	0.355	indeterminate
SaProt	LLR -14.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -2.6, phastCons 0.011
Regional constraint	o/e 1.15	unconstrained · MANE · 1,902 bp · p 0.00072 · regional, not allelic
Overall
CADD	18.13	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.121% African / African-American · 78/64,608 alleles

Filtering AF 0.0991% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0911%

Overall 0.00689% 89/1,290,968 alleles · rare exomes 34/1,138,918 · genomes 55/152,050 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.121%	828
Admixed American	0.0199%	5,033
Remaining individualsnot grpmax-eligible	0.0123%	8,119

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: ANKRD65
Protein: p.Arg91Pro
Coding: c.272G>C
MANE Select: NM_001145210
Type: single nucleotide variant
Location: chr1:1420530 (GRCh38)
Gene constraint: LOEUF 1.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.07

Full ANKRD65 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD65 p.Ala106Val Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala115Thr Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala147Asp Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala162Pro Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala168Thr Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala170Val Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala180Val Uncertain significance ★ ⚠ same type
ANKRD65 p.Ala198Ser 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/ankrd65-p-arg91pro (accessed [today's date]).

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