Is C9 p.Ser460Tyr (c.1379C>A) pathogenic?

C9 p.Ser460Tyr (c.1379C>A) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.1614); Very rare (popmax 0.00659%, sas).

How common is C9 p.Ser460Tyr (c.1379C>A) in the general population?

C9 p.Ser460Tyr (c.1379C>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about C9 p.Ser460Tyr (c.1379C>A)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

C9 p.Ser460Tyr

c.1379C>A · rs760939510 · VCV1345646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -3.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.06, phastCons 0.87
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	22.2	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 0.00659% South Asian · 6/91,082 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000411% 6/1,461,570 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.Ser460Tyr
Coding: c.1379C>A
MANE Select: NM_001737
dbSNP: rs760939510
Type: single nucleotide variant
Location: chr5:39306654 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 460: the macpf domain; an α-helix

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

Similar variants

C9 p.Ser460Thr Uncertain significance ★ ⚠ 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-ser460tyr (accessed [today's date]).

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