Is C2 p.Pro86Ser (c.256C>T) pathogenic?

C2 p.Pro86Ser (c.256C>T) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). AlphaMissense: likely benign (0.0809); Very rare (popmax 0.00671%, amr).

How common is C2 p.Pro86Ser (c.256C>T) in the general population?

C2 p.Pro86Ser (c.256C>T) is very rare (popmax 0.00671%, amr) (gnomAD).

What do computational predictors say about C2 p.Pro86Ser (c.256C>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

C2 p.Pro86Ser

c.256C>T · VCV3709260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00671%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.29	GERP -0.56, phastCons 0.16
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	18.36	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 0.00671% Admixed American · 4/59,570 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00224% 36/1,605,094 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00671%	14,892
Remaining individualsnot grpmax-eligible	0.00321%	31,161
European (non-Finnish)	0.00229%	43,651
South Asian	0.00221%	45,186
African / African-American	0.00134%	74,872

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.Pro86Ser
Coding: c.256C>T
MANE Select: NM_000063
Type: single nucleotide variant
Location: chr6:31928164 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 86: the sushi 1 domain; a β-strand

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-pro86ser (accessed [today's date]).

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