Is C7 p.His559Arg (c.1676A>G) pathogenic?

C7 p.His559Arg (c.1676A>G) is classified Likely benign in C7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1576); Rare (popmax 0.323%, afr).

How common is C7 p.His559Arg (c.1676A>G) in the general population?

C7 p.His559Arg (c.1676A>G) is rare (popmax 0.323%, afr) (gnomAD).

What do computational predictors say about C7 p.His559Arg (c.1676A>G)?

AlphaMissense predicts likely benign (score 0.1576) — an in-silico prediction, not a clinical call.

C7 p.His559Arg

c.1676A>G · rs141595076 · VCV1151171

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1576 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.323%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1576	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Overall
CADD	23.5	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 0.323% African / African-American · 239/73,986 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.276%

Overall 0.0182% 281/1,546,664 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.323%	310
Remaining individualsnot grpmax-eligible	0.0369%	2,713
Middle Eastern	0.034%	2,941
Admixed American	0.0295%	3,394
European (non-Finnish)	0.000176%	569,531

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.His559Arg
Coding: c.1676A>G
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs141595076
Type: single nucleotide variant
Location: chr5:40962099 (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 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
C7 p.Ala359Thr 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/c7-p-his559arg (accessed [today's date]).

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