Is C2CD6 p.Met330Thr (c.989T>C) pathogenic?

C2CD6 p.Met330Thr (c.989T>C) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.9676); Rare (popmax 0.136%, nfe).

How common is C2CD6 p.Met330Thr (c.989T>C) in the general population?

C2CD6 p.Met330Thr (c.989T>C) is rare (popmax 0.136%, nfe) (gnomAD).

What do computational predictors say about C2CD6 p.Met330Thr (c.989T>C)?

AlphaMissense predicts likely pathogenic (score 0.9676) — an in-silico prediction, not a clinical call.

C2CD6 p.Met330Thr

c.989T>C · rs138185225 · VCV3135978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9676 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9676	likely pathogenic · top 2% in C2CD6
REVEL	0.124	moderately benign-leaning
SaProt	LLR -3.83	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	22.6	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 0.136% European (non-Finnish) · 1,502/1,105,476 alleles

Filtering AF 0.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.104% 1,558/1,498,314 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.136%	736
Remaining individualsnot grpmax-eligible	0.0448%	2,231
African / African-American	0.0212%	4,715
Finnishnot grpmax-eligible	0.0158%	6,347
Admixed American	0.00847%	11,813
South Asian	0.00243%	41,161

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: C2CD6
Protein: p.Met330Thr
Coding: c.989T>C
MANE Select: NM_001168221
dbSNP: rs138185225
Type: single nucleotide variant
Location: chr2:201547599 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82

Full C2CD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD6 p.Ala1682Thr Uncertain significance ★ same type
C2CD6 p.Ala427Gly Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Pro Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Ser Uncertain significance ★ ⚠ same type
C2CD6 p.Ala646Ser Uncertain significance ★ same type
C2CD6 p.Ala827Asp Uncertain significance ★ same type
C2CD6 p.Arg1134Cys Uncertain significance ★ same type
C2CD6 p.Arg1134His 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/c2cd6-p-met330thr (accessed [today's date]).

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