Is C6 p.Thr327Met (c.980C>T) pathogenic?

C6 p.Thr327Met (c.980C>T) is classified Benign in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0534); Rare (popmax 0.712%, eas).

How common is C6 p.Thr327Met (c.980C>T) in the general population?

C6 p.Thr327Met (c.980C>T) is rare (popmax 0.712%, eas) (gnomAD).

What do computational predictors say about C6 p.Thr327Met (c.980C>T)?

AlphaMissense predicts likely benign (score 0.0534) — an in-silico prediction, not a clinical call.

C6 p.Thr327Met

c.980C>T · rs151296032 · VCV2045041

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0534 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.712%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0534	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -3.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -3.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	6.197	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 0.712% East Asian · 319/44,804 alleles

Filtering AF 0.648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.622%

Overall 0.0455% 734/1,613,028 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.842%	119
East Asiangrpmax	0.712%	140
Remaining individualsnot grpmax-eligible	0.0784%	1,275
Middle Eastern	0.0167%	5,986
South Asian	0.011%	9,106
European (non-Finnish)	0.00873%	11,448
Admixed American	0.005%	20,004

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr327Met
Coding: c.980C>T
MANE Select: NM_000065
dbSNP: rs151296032
Type: single nucleotide variant
Location: chr5:41176663 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 327: a β-strand; the macpf domain

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

Similar variants

C6 p.Thr327= Likely benign ★ same residue
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

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-thr327met (accessed [today's date]).

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