Is ARK2C p.Ser75Arg (c.223A>C) pathogenic?

ARK2C p.Ser75Arg (c.223A>C) is classified Uncertain significance in ARK2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). AlphaMissense: ambiguous (0.4344); Absent from gnomAD v4.1.

How common is ARK2C p.Ser75Arg (c.223A>C) in the general population?

ARK2C p.Ser75Arg (c.223A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARK2C p.Ser75Arg (c.223A>C)?

AlphaMissense predicts ambiguous (score 0.4344) — an in-silico prediction, not a clinical call.

ARK2C p.Ser75Arg

c.223A>C · rs2511291124 · VCV2287014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4344 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4344	ambiguous
REVEL	0.11	moderately benign-leaning
SaProt	LLR -6.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 122 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARK2C
Protein: p.Ser75Arg
Coding: c.223A>C
MANE Select: NM_152470
dbSNP: rs2511291124
Type: single nucleotide variant
Location: chr18:46433351 (GRCh38)
Structure: AlphaFold pLDDT 57.50 · 9 PDB
Residue 75: the 'disordered' region

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.Arg138Cys 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

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-ser75arg (accessed [today's date]).

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