Is C6 p.Pro233Leu (c.698C>T) pathogenic?

C6 p.Pro233Leu (c.698C>T) is classified Uncertain significance in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: ambiguous (0.5215); Ultra-rare (popmax 0.0132%, sas).

How common is C6 p.Pro233Leu (c.698C>T) in the general population?

C6 p.Pro233Leu (c.698C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about C6 p.Pro233Leu (c.698C>T)?

AlphaMissense predicts ambiguous (score 0.5215) — an in-silico prediction, not a clinical call.

C6 p.Pro233Leu

c.698C>T · rs776129858 · VCV1401153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5215 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Computational evidence

Protein change
AlphaMissense	0.5215	ambiguous
REVEL	0.512	indeterminate
SaProt	LLR -12.25	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.85, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	25.3	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 0.0132% South Asian · 12/91,076 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00304% 49/1,613,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,590
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.00254%	39,331
Admixed American	0.00167%	59,954
Finnishnot grpmax-eligible	0.00156%	64,006
African / African-American	0.00134%	74,900

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.Pro233Leu
Coding: c.698C>T
MANE Select: NM_000065
dbSNP: rs776129858
Type: single nucleotide variant
Location: chr5:41186098 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 233: the macpf domain

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

Similar variants

C6 p.Pro233Ser Uncertain significance ★ ⚠ same residue
C6 p.Pro233= 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

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-pro233leu (accessed [today's date]).

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