Is ANKRD35 p.Arg739Pro (c.2216G>C) pathogenic?

ANKRD35 p.Arg739Pro (c.2216G>C) is classified Uncertain significance in ANKRD35 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.6539); Ultra-rare (popmax 0.0575%, afr).

How common is ANKRD35 p.Arg739Pro (c.2216G>C) in the general population?

ANKRD35 p.Arg739Pro (c.2216G>C) is ultra-rare (popmax 0.0575%, afr) (gnomAD).

What do computational predictors say about ANKRD35 p.Arg739Pro (c.2216G>C)?

AlphaMissense predicts likely pathogenic (score 0.6539) — an in-silico prediction, not a clinical call.

ANKRD35 p.Arg739Pro

c.2216G>C · rs142514686 · VCV2262788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6539 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0575%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.6539	likely pathogenic
SaProt	LLR -11.34	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.006	GERP 0.77
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.78 · regional, not allelic
Overall
CADD	14.42	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 0.0575% African / African-American · 43/74,842 alleles

Filtering AF 0.0438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00317% 51/1,609,434 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0575%	1,741
Admixed American	0.00677%	14,769
Remaining individualsnot grpmax-eligible	0.00482%	20,763
European (non-Finnish)	8.49e-05%	1,177,933

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: ANKRD35
Protein: p.Arg739Pro
Coding: c.2216G>C
MANE Select: NM_144698
dbSNP: rs142514686
Type: single nucleotide variant
Location: chr1:145872553 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43

Full ANKRD35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD35 p.Arg739Gln Uncertain significance ★ ⚠ same residue
ANKRD35 p.Ala133Val Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala144Thr Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala202Gly Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala212Thr Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala241Ser Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala480Ser Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala486Glu 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/ankrd35-p-arg739pro (accessed [today's date]).

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