Is ANKRD34C p.Arg243His (c.728G>A) pathogenic?

ANKRD34C p.Arg243His (c.728G>A) is classified Uncertain significance in ANKRD34C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.1297); Ultra-rare (popmax 0.0123%, afr).

How common is ANKRD34C p.Arg243His (c.728G>A) in the general population?

ANKRD34C p.Arg243His (c.728G>A) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

What do computational predictors say about ANKRD34C p.Arg243His (c.728G>A)?

AlphaMissense predicts likely benign (score 0.1297) — an in-silico prediction, not a clinical call.

ANKRD34C p.Arg243His

c.728G>A · VCV3398656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1297 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1297	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.64	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 1.7	GERP -1.7, phastCons 0.087
Regional constraint	o/e 0.95	unconstrained · MANE · 1,258 bp · p 0.23 · regional, not allelic
Overall
CADD	18.34	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 0.0123% African / African-American · 9/73,014 alleles

Filtering AF 0.00805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00748%

Overall 0.00851% 132/1,551,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,113
Finnishnot grpmax-eligible	0.01%	9,980
European (non-Finnish)	0.0095%	10,523
Remaining individualsnot grpmax-eligible	0.00666%	15,022
East Asian	0.00244%	40,928
South Asian	0.00238%	42,024
Admixed American	0.00196%	50,980

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: ANKRD34C
Protein: p.Arg243His
Coding: c.728G>A
MANE Select: NM_001146341
Type: single nucleotide variant
Location: chr15:79294012 (GRCh38)
Gene constraint: LOEUF 1.761 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 54.66

Full ANKRD34C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD34C p.Ala186Val Uncertain significance ★ ⚠ same type
ANKRD34C p.Ala242Ser Uncertain significance ★ ⚠ same type
ANKRD34C p.Ala259Val Uncertain significance ★ ⚠ same type
ANKRD34C p.Ala264Thr Uncertain significance ★ ⚠ same type
ANKRD34C p.Arg117Cys Uncertain significance ★ ⚠ same type
ANKRD34C p.Arg117His Uncertain significance ★ ⚠ same type
ANKRD34C p.Arg179Lys Uncertain significance ★ ⚠ same type
ANKRD34C p.Arg268His 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/ankrd34c-p-arg243his (accessed [today's date]).

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