Is C6 p.Thr702Met (c.2105C>T) pathogenic?

C6 p.Thr702Met (c.2105C>T) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0798); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Thr702Met (c.2105C>T)?

C6 p.Thr702Met (c.2105C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Thr702Met (c.2105C>T) in the general population?

C6 p.Thr702Met (c.2105C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about C6 p.Thr702Met (c.2105C>T)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

C6 p.Thr702Met

c.2105C>T · rs759974891 · VCV1436325

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP -2.4, phastCons 0.061
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	13.11	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 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00285% 46/1,613,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
Remaining individualsnot grpmax-eligible	0.00801%	12,488
South Asian	0.00769%	13,009
East Asian	0.00669%	14,942
African / African-American	0.00534%	18,722
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
European (non-Finnish)	0.00204%	49,138
Admixed American	0.00167%	59,946

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.Thr702Met
Coding: c.2105C>T
MANE Select: NM_000065
dbSNP: rs759974891
Type: single nucleotide variant
Location: chr5:41153995 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 702: the sushi 2 domain; the 'c5b-binding domain' region; the 'ccp 2' region

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.Thr702= Likely benign ★ same residue
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same condition
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same condition
C6 p.Ala500Ser 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

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-thr702met (accessed [today's date]).

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