Is ARB2A p.Ser322Cys (c.965C>G) pathogenic?

ARB2A p.Ser322Cys (c.965C>G) is classified Uncertain significance in ARB2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-23). AlphaMissense: likely pathogenic (0.9784); Very rare (popmax 0.00267%, afr).

How common is ARB2A p.Ser322Cys (c.965C>G) in the general population?

ARB2A p.Ser322Cys (c.965C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ARB2A p.Ser322Cys (c.965C>G)?

AlphaMissense predicts likely pathogenic (score 0.9784) — an in-silico prediction, not a clinical call.

ARB2A p.Ser322Cys

c.965C>G · VCV3420084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9784	likely pathogenic
REVEL	0.596	indeterminate
SaProt	LLR -10.47	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 454 kb · p 0.66 · regional, not allelic
Overall
CADD	29.3	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 0.00267% African / African-American · 2/74,992 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000342% 5/1,461,304 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,496
European (non-Finnish)	0.000254%	393,196

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: ARB2A
Protein: p.Ser322Cys
Coding: c.965C>G
MANE Select: NM_032042
Type: single nucleotide variant
Location: chr5:93784441 (GRCh38)
Structure: AlphaFold pLDDT 84.01
Residue 322: a UniProt-annotated variant site (found in a patient with charges; uncertain significance)

Full ARB2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARB2A p.Ala271Val Uncertain significance ★ ⚠ same type
ARB2A p.Ala283Val Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Gly Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Trp Uncertain significance ★ ⚠ same type
ARB2A p.Arg240Gln Uncertain significance ★ ⚠ same type
ARB2A p.Arg241Cys Uncertain significance ★ ⚠ same type
ARB2A p.Arg241His Uncertain significance ★ ⚠ same type
ARB2A p.Arg306Gln 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/arb2a-p-ser322cys (accessed [today's date]).

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