Is C9 p.Ser129Leu (c.386C>T) pathogenic?

C9 p.Ser129Leu (c.386C>T) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.3328); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C9 p.Ser129Leu (c.386C>T)?

C9 p.Ser129Leu (c.386C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Ser129Leu (c.386C>T) in the general population?

C9 p.Ser129Leu (c.386C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C9 p.Ser129Leu (c.386C>T)?

AlphaMissense predicts likely benign (score 0.3328) — an in-silico prediction, not a clinical call.

C9 p.Ser129Leu

c.386C>T · VCV4217480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3328 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3328	likely benign
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt 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	28.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C9
Protein: p.Ser129Leu
Coding: c.386C>T
MANE Select: NM_001737
Type: single nucleotide variant
Location: chr5:39341236 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 129: a disulfide bond; the ldl-receptor class a 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.Ser129= Benign ★★ 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-ser129leu (accessed [today's date]).

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