Is C9 p.Pro90Leu (c.269C>T) pathogenic?

C9 p.Pro90Leu (c.269C>T) is classified Uncertain significance in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-26). AlphaMissense: likely benign (0.2082); Very rare (popmax 0.00415%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C9 p.Pro90Leu (c.269C>T)?

C9 p.Pro90Leu (c.269C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Pro90Leu (c.269C>T) in the general population?

C9 p.Pro90Leu (c.269C>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about C9 p.Pro90Leu (c.269C>T)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

C9 p.Pro90Leu

c.269C>T · rs745883875 · VCV1433238

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2082	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -11.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	26.8	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 0.00415% European (non-Finnish) · 49/1,179,364 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00316% 51/1,613,316 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,069
Remaining individualsnot grpmax-eligible	0.0016%	62,464
South Asian	0.0011%	91,072

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.Pro90Leu
Coding: c.269C>T
MANE Select: NM_001737
dbSNP: rs745883875
Type: single nucleotide variant
Location: chr5:39341615 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 90: a disulfide bond; the tsp type-1 domain

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.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
C9 p.Asn182Lys 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-pro90leu (accessed [today's date]).

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