Is ANKRD34C p.Cys185Arg (c.553T>C) pathogenic?

ANKRD34C p.Cys185Arg (c.553T>C) is classified Uncertain significance in ANKRD34C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.3337); Very rare (popmax 0.000262%, nfe).

How common is ANKRD34C p.Cys185Arg (c.553T>C) in the general population?

ANKRD34C p.Cys185Arg (c.553T>C) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about ANKRD34C p.Cys185Arg (c.553T>C)?

AlphaMissense predicts likely benign (score 0.3337) — an in-silico prediction, not a clinical call.

ANKRD34C p.Cys185Arg

c.553T>C · VCV4640903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3337	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -4.54	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 2.6	GERP -0.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,258 bp · p 0.23 · regional, not allelic
Overall
CADD	19.06	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 0.000262% European (non-Finnish) · 3/1,146,984 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000214% 3/1,399,404 alleles · very rare

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.Cys185Arg
Coding: c.553T>C
MANE Select: NM_001146341
Type: single nucleotide variant
Location: chr15:79293837 (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.Arg243His 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-cys185arg (accessed [today's date]).

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