Is C6 p.Asp336Gly (c.1007A>G) pathogenic?

C6 p.Asp336Gly (c.1007A>G) is classified Uncertain significance in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: likely benign (0.1326); Very rare (popmax 0.0022%, sas).

How common is C6 p.Asp336Gly (c.1007A>G) in the general population?

C6 p.Asp336Gly (c.1007A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about C6 p.Asp336Gly (c.1007A>G)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

C6 p.Asp336Gly

c.1007A>G · rs1412266338 · VCV2089936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.2	GERP 0.59, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	19.54	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 0.0022% South Asian · 2/91,066 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000274% 4/1,461,598 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,533
European (non-Finnish)	0.00017%	589,922

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.Asp336Gly
Coding: c.1007A>G
MANE Select: NM_000065
dbSNP: rs1412266338
Type: single nucleotide variant
Location: chr5:41176636 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 336: an α-helix; the macpf domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Arg606Ter Pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same type
C6 p.Ala500Ser 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/c6-p-asp336gly (accessed [today's date]).

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