Is C6 p.Ala500Ser (c.1498G>T) pathogenic?

C6 p.Ala500Ser (c.1498G>T) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-01). AlphaMissense: likely benign (0.1293); Ultra-rare (popmax 0.0417%, amr); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Ala500Ser (c.1498G>T)?

C6 p.Ala500Ser (c.1498G>T) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Ala500Ser (c.1498G>T) in the general population?

C6 p.Ala500Ser (c.1498G>T) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

What do computational predictors say about C6 p.Ala500Ser (c.1498G>T)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

C6 p.Ala500Ser

c.1498G>T · rs370054003 · VCV1175125

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -7.40	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	28.0	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 0.0417% Admixed American · 25/59,942 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00781% 126/1,613,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,398
Middle Eastern	0.0329%	3,038
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)	0.00763%	13,109
African / African-American	0.00267%	37,439
Finnishnot grpmax-eligible	0.00156%	64,018

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: C6
Protein: p.Ala500Ser
Coding: c.1498G>T
MANE Select: NM_000065
dbSNP: rs370054003
Type: single nucleotide variant
Location: chr5:41160328 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 500: an α-helix; a disulfide bond; the macpf domain

Full C6 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

C6 p.Ala500= Likely benign ★ same residue
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same condition
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same condition
C6 p.Arg108His Uncertain significance ★★ ⚠ same condition
C6 p.Arg145His Uncertain significance ★★ ⚠ same condition
C6 p.Arg150His Uncertain significance ★★ ⚠ same condition
C6 p.Arg182Gln Uncertain significance ★★ ⚠ same condition
C6 p.Arg356Gln 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/c6-p-ala500ser (accessed [today's date]).

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