Is ARK2C p.Arg138Cys (c.412C>T) pathogenic?

ARK2C p.Arg138Cys (c.412C>T) is classified Uncertain significance in ARK2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-26). AlphaMissense: likely benign (0.1519); Very rare (popmax 0.00266%, afr).

How common is ARK2C p.Arg138Cys (c.412C>T) in the general population?

ARK2C p.Arg138Cys (c.412C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about ARK2C p.Arg138Cys (c.412C>T)?

AlphaMissense predicts likely benign (score 0.1519) — an in-silico prediction, not a clinical call.

ARK2C p.Arg138Cys

c.412C>T · rs752024290 · VCV3235456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1519	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 122 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	31.0	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 0.00266% African / African-American · 2/75,056 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00041% 6/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,528
European (non-Finnish)	0.000339%	295,005

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: ARK2C
Protein: p.Arg138Cys
Coding: c.412C>T
MANE Select: NM_152470
dbSNP: rs752024290
Type: single nucleotide variant
Location: chr18:46435323 (GRCh38)
Structure: AlphaFold pLDDT 57.50 · 9 PDB

Full ARK2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARK2C p.Ala157Thr Uncertain significance ★ ⚠ same type
ARK2C p.Arg211Gln Uncertain significance ★ ⚠ same type
ARK2C p.Arg236Gln Uncertain significance ★ ⚠ same type
ARK2C p.Asn227Thr Uncertain significance ★ ⚠ same type
ARK2C p.Asp345Asn Uncertain significance ★ ⚠ same type
ARK2C p.Gln147His Uncertain significance ★ ⚠ same type
ARK2C p.Gln174Glu Uncertain significance ★ ⚠ same type
ARK2C p.Gln46Pro 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/ark2c-p-arg138cys (accessed [today's date]).

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