Is C9 p.Val199Leu (c.595G>C) pathogenic?

C9 p.Val199Leu (c.595G>C) is classified Uncertain significance in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-17). AlphaMissense: likely benign (0.2663); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with C9 p.Val199Leu (c.595G>C)?

C9 p.Val199Leu (c.595G>C) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Val199Leu (c.595G>C) in the general population?

C9 p.Val199Leu (c.595G>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about C9 p.Val199Leu (c.595G>C)?

AlphaMissense predicts likely benign (score 0.2663) — an in-silico prediction, not a clinical call.

C9 p.Val199Leu

c.595G>C · rs753583142 · VCV1384149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2663	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.44	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 0.26	GERP -1.8, phastCons 0.009
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	15.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.01% Admixed American · 6/60,018 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00223% 36/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.00237%	42,137

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.Val199Leu
Coding: c.595G>C
MANE Select: NM_001737
dbSNP: rs753583142
Type: single nucleotide variant
Location: chr5:39331696 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 199: the macpf domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C9 p.Val199Met Uncertain significance ★ ⚠ same residue
C9 p.Ala497Val Uncertain significance ★★ ⚠ same condition
C9 p.Arg139His Uncertain significance ★★ ⚠ same condition
C9 p.Arg154Gln Uncertain significance ★★ ⚠ same condition
C9 p.Arg154Pro Uncertain significance ★★ ⚠ same condition
C9 p.Arg369Gln Uncertain significance ★★ ⚠ same condition
C9 p.Arg369Trp Uncertain significance ★★ ⚠ same condition
C9 p.Arg63His Uncertain significance ★★ ⚠ same condition

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-val199leu (accessed [today's date]).

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