Is C2CD5 p.Arg371His (c.1112G>A) pathogenic?

C2CD5 p.Arg371His (c.1112G>A) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely pathogenic (0.8131); Ultra-rare (popmax 0.0659%, mid).

How common is C2CD5 p.Arg371His (c.1112G>A) in the general population?

C2CD5 p.Arg371His (c.1112G>A) is ultra-rare (popmax 0.0659%, mid) (gnomAD).

What do computational predictors say about C2CD5 p.Arg371His (c.1112G>A)?

AlphaMissense predicts likely pathogenic (score 0.8131) — an in-silico prediction, not a clinical call.

C2CD5 p.Arg371His

c.1112G>A · rs142421095 · VCV2354863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8131 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8131	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -12.54	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.44 · regional, not allelic
Overall
CADD	32.0	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 0.0659% Middle Eastern · 4/6,074 alleles

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

Overall 0.00435% 70/1,609,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0659%	1,518
Remaining individualsnot grpmax-eligible	0.00802%	12,465
Admixed American	0.005%	19,998
European (non-Finnish)	0.00485%	20,633
Finnishnot grpmax-eligible	0.00156%	63,990

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: C2CD5
Protein: p.Arg371His
Coding: c.1112G>A
MANE Select: NM_001286176
dbSNP: rs142421095
Type: single nucleotide variant
Location: chr12:22506746 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34

Full C2CD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD5 p.Arg371Cys Uncertain significance ★ ⚠ same residue
C2CD5 p.Ala21Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala242Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala252Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala342Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala355Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala405Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala433Val 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/c2cd5-p-arg371his (accessed [today's date]).

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