Is C7 p.Arg222His (c.665G>A) pathogenic?

C7 p.Arg222His (c.665G>A) is classified Benign/Likely benign in C7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0864); Common (popmax 9.1%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C7 p.Arg222His (c.665G>A)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

C7 p.Arg222His

Q: How common is C7 p.Arg222His (c.665G>A) in the general population?

C7 p.Arg222His (c.665G>A) is common (popmax 9.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.665G>A · rs75345202 · VCV1170702

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.47	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 -4.7	GERP -4.9
Overall
CADD	2.05	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

Grpmax group 9.1% East Asian · 4,057/44,572 alleles

Filtering AF 8.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.77%

Overall 0.383% 6,159/1,607,530 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	9.1%	11
Admixed American	2.31%	43
Remaining individualsnot grpmax-eligible	0.525%	190
South Asian	0.264%	378
African / African-American	0.0789%	1,268
Middle Eastern	0.033%	3,027
European (non-Finnish)	0.00935%	10,698
Finnishnot grpmax-eligible	0.00313%	31,950

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: C7
Protein: p.Arg222His
Coding: c.665G>A
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs75345202
Type: single nucleotide variant
Location: chr5:40945295 (GRCh38)
Structure: AlphaFold pLDDT 89.67 · 6 PDB

Full C7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C7 p.Arg222Cys Uncertain significance ★ ⚠ same residue
C7 c.281-1G>T Pathogenic/Likely pathogenic ★★ same type
C7 c.63-1G>A Pathogenic ★★ same type
C7 c.739-2A>G Likely pathogenic ★★ same type
C7 p.Arg402Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gly379Arg Pathogenic/Likely pathogenic ★★ same type
C7 p.Trp205Ter Pathogenic/Likely pathogenic ★★ 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/c7-p-arg222his (accessed [today's date]).

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