Is ANKRD65 p.Arg75Pro (c.224G>C) pathogenic?

ANKRD65 p.Arg75Pro (c.224G>C) is classified Uncertain significance in ANKRD65 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely pathogenic (0.9422); Very rare (popmax 0.00159%, nfe).

How common is ANKRD65 p.Arg75Pro (c.224G>C) in the general population?

ANKRD65 p.Arg75Pro (c.224G>C) is very rare (popmax 0.00159%, nfe) (gnomAD).

What do computational predictors say about ANKRD65 p.Arg75Pro (c.224G>C)?

AlphaMissense predicts likely pathogenic (score 0.9422) — an in-silico prediction, not a clinical call.

ANKRD65 p.Arg75Pro

c.224G>C · rs1289906629 · VCV2468262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00159%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9422	likely pathogenic · top 2% in ANKRD65
REVEL	0.378	indeterminate
SaProt	LLR -16.25	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 7	GERP -1.1, phastCons 0.85
Regional constraint	o/e 1.15	unconstrained · MANE · 1,902 bp · p 0.00072 · regional, not allelic
Overall
CADD	23.1	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 0.00159% European (non-Finnish) · 17/1,068,642 alleles

Filtering AF 0.000969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000792%

Overall 0.00138% 19/1,376,742 alleles · very rare exomes 18/1,224,642 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00379%	26,414
European (non-Finnish)grpmax	0.00159%	62,861

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg75Pro
Coding: c.224G>C
MANE Select: NM_001145210
dbSNP: rs1289906629
Type: single nucleotide variant
Location: chr1:1420578 (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.Arg75Gln Uncertain significance ★ ⚠ same residue
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

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-arg75pro (accessed [today's date]).

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