Is C9 p.Ile203Val (c.607A>G) pathogenic?

C9 p.Ile203Val (c.607A>G) is classified Benign/Likely benign in C9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0763); Common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C9 p.Ile203Val (c.607A>G)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

C9 p.Ile203Val

Q: How common is C9 p.Ile203Val (c.607A>G) in the general population?

C9 p.Ile203Val (c.607A>G) is common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.607A>G · rs13361416 · VCV1167485

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.46	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 -2.2	GERP -3.9
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	0.029	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 10.1% African / African-American · 7,590/74,978 alleles

Filtering AF 9.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.85%

Overall 0.63% 10,170/1,613,886 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.1%	10
Middle Eastern	1.22%	82
Admixed American	1%	100
Remaining individualsnot grpmax-eligible	0.942%	106
Ashkenazi Jewishnot grpmax-eligible	0.351%	285
European (non-Finnish)	0.0995%	1,005
South Asian	0.0406%	2,461

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: C9
Protein: p.Ile203Val
Coding: c.607A>G
MANE Select: NM_001737
dbSNP: rs13361416
Type: single nucleotide variant
Location: chr5:39331684 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 203: the macpf domain; a UniProt-annotated variant site (in); a β-strand

Full C9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C9 p.Ile203= Likely benign ★ same residue
C9 c.871-2A>G Likely pathogenic ★★ same type
C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg86Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same type
C9 c.1240+5G>T 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/c9-p-ile203val (accessed [today's date]).

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