Is ANKRD65 p.Arg108Pro (c.323G>C) pathogenic?

ANKRD65 p.Arg108Pro (c.323G>C) is classified Uncertain significance in ANKRD65 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9182); Very rare (popmax 0.000395%, nfe).

How common is ANKRD65 p.Arg108Pro (c.323G>C) in the general population?

ANKRD65 p.Arg108Pro (c.323G>C) is very rare (popmax 0.000395%, nfe) (gnomAD).

What do computational predictors say about ANKRD65 p.Arg108Pro (c.323G>C)?

AlphaMissense predicts likely pathogenic (score 0.9182) — an in-silico prediction, not a clinical call.

ANKRD65 p.Arg108Pro

c.323G>C · rs2523655439 · VCV2337935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000395%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9182	likely pathogenic · top 4% in ANKRD65
REVEL	0.438	indeterminate
SaProt	LLR -15.22	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 0.98	GERP -2.6, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,902 bp · p 0.00072 · regional, not allelic
Overall
CADD	21.0	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 0.000395% European (non-Finnish) · 4/1,013,788 alleles

Filtering AF 9.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2e-05%

Overall 0.000315% 4/1,269,654 alleles · very rare exomes 4/1,117,950 · genomes 0/151,704 · joint denominator

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.Arg108Pro
Coding: c.323G>C
MANE Select: NM_001145210
dbSNP: rs2523655439
Type: single nucleotide variant
Location: chr1:1420479 (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-arg108pro (accessed [today's date]).

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