Is C2 p.Met648Thr (c.1943T>C) pathogenic?

C2 p.Met648Thr (c.1943T>C) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-06). AlphaMissense: likely benign (0.0537); Very rare (popmax 0.00267%, afr).

How common is C2 p.Met648Thr (c.1943T>C) in the general population?

C2 p.Met648Thr (c.1943T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about C2 p.Met648Thr (c.1943T>C)?

AlphaMissense predicts likely benign (score 0.0537) — an in-silico prediction, not a clinical call.

C2 p.Met648Thr

c.1943T>C · rs764248742 · VCV1965320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0537	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	acceptor loss, 18 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -3.5	GERP -3.2
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	0.026	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 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,612,962 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,462
South Asian	0.0011%	91,088
European (non-Finnish)	8.47e-05%	1,180,040

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: C2
Protein: p.Met648Thr
Coding: c.1943T>C
MANE Select: NM_000063
dbSNP: rs764248742
Type: single nucleotide variant
Location: chr6:31944767 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 648: a β-strand; a disulfide bond; the peptidase s1 domain

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/c2-p-met648thr (accessed [today's date]).

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