Is C5 p.Val145Ile (c.433G>A) pathogenic?

C5 p.Val145Ile (c.433G>A) is classified Benign/Likely benign in C5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0966); Common (popmax 24.5%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C5 p.Val145Ile (c.433G>A)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

C5 p.Val145Ile

Q: How common is C5 p.Val145Ile (c.433G>A) in the general population?

C5 p.Val145Ile (c.433G>A) is common (popmax 24.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.433G>A · rs17216529 · VCV1167059

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 24.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -7.77	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	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	23.1	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 24.5% African / African-American · 17,627/71,964 alleles

Filtering AF 24.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.1%

Overall 7.66% 114,757/1,498,624 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	24.5%	4
East Asian	18.6%	5
Remaining individualsnot grpmax-eligible	8.01%	12
Finnishnot grpmax-eligible	7.53%	13
Amishnot grpmax-eligible	6.8%	15
European (non-Finnish)	6.69%	15
Ashkenazi Jewishnot grpmax-eligible	5.59%	18
Admixed American	4.57%	22
Middle Eastern	3.81%	26
South Asian	2.99%	33

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: C5
Protein: p.Val145Ile
Coding: c.433G>A
MANE Select: NM_001735
dbSNP: rs17216529
Type: single nucleotide variant
Location: chr9:121037940 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 145: a UniProt-annotated variant site (in c5d); a UniProt-annotated variant site (in); a β-strand

Full C5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C5 p.Val145= Likely benign ★★ same residue
C5 c.2257+1G>A Likely pathogenic ★★ same type
C5 c.4679-2A>G Likely pathogenic ★★ same type
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same type
C5 p.Gln19Ter Pathogenic ★★ same type
C5 p.Glu1437Ter Pathogenic/Likely pathogenic ★★ same type
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same type
C5 c.2059+3A>G 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/c5-p-val145ile (accessed [today's date]).

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