Is C2 p.Arg88His (c.263G>A) pathogenic?

C2 p.Arg88His (c.263G>A) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1014); Ultra-rare (popmax 0.0658%, mid).

How common is C2 p.Arg88His (c.263G>A) in the general population?

C2 p.Arg88His (c.263G>A) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about C2 p.Arg88His (c.263G>A)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

C2 p.Arg88His

c.263G>A · rs771240344 · VCV2403182

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.05	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 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.9	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 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00384% 62/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
South Asian	0.00659%	15,181
European (non-Finnish)	0.00415%	24,082
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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: C2
Protein: p.Arg88His
Coding: c.263G>A
MANE Select: NM_000063
dbSNP: rs771240344
Type: single nucleotide variant
Location: chr6:31928738 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 88: the sushi 2 domain; a β-strand

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2 p.Arg88Cys Uncertain significance ★ ⚠ same residue
C2 c.1902+5G>A Uncertain significance ★★ same type
C2 c.2029+5G>A Uncertain significance ★★ same type
C2 p.Ala363Thr Uncertain significance ★★ ⚠ same type
C2 p.Ala682Glu Uncertain significance ★★ ⚠ same type
C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
C2 p.Arg129His Uncertain significance ★★ ⚠ same type
C2 p.Arg174Cys 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/c2-p-arg88his (accessed [today's date]).

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