Is C9 p.Phe243Cys (c.728T>G) pathogenic?

C9 p.Phe243Cys (c.728T>G) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: ambiguous (0.4791); Very rare (popmax 6.85e-05%); Associated with Inborn genetic diseases.

What condition is associated with C9 p.Phe243Cys (c.728T>G)?

C9 p.Phe243Cys (c.728T>G) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Phe243Cys (c.728T>G) in the general population?

C9 p.Phe243Cys (c.728T>G) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about C9 p.Phe243Cys (c.728T>G)?

AlphaMissense predicts ambiguous (score 0.4791) — an in-silico prediction, not a clinical call.

C9 p.Phe243Cys

c.728T>G · rs1753561767 · VCV3136102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4791	ambiguous
REVEL	0.11	moderately benign-leaning
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -0.4, phastCons 0.87
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	21.0	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 6.85e-05%

Overall 6.85e-05% 1/1,460,500 alleles · very rare

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.Phe243Cys
Coding: c.728T>G
MANE Select: NM_001737
dbSNP: rs1753561767
Type: single nucleotide variant
Location: chr5:39315917 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 243: the macpf 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-phe243cys (accessed [today's date]).

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