Is C8G p.Pro183Leu (c.548C>T) pathogenic?

C8G p.Pro183Leu (c.548C>T) is classified Uncertain significance in C8G (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.6473); Very rare (popmax 0.004%, afr).

How common is C8G p.Pro183Leu (c.548C>T) in the general population?

C8G p.Pro183Leu (c.548C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about C8G p.Pro183Leu (c.548C>T)?

AlphaMissense predicts likely pathogenic (score 0.6473) — an in-silico prediction, not a clinical call.

C8G p.Pro183Leu

c.548C>T · rs769430206 · VCV2385046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6473 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6473	likely pathogenic
REVEL	0.269	benign-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,457 bp · p 0.046 · regional, not allelic
Overall
CADD	24.3	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 0.004% African / African-American · 3/74,908 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.0018% 29/1,612,848 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,969
European (non-Finnish)	0.00212%	47,193
Remaining individualsnot grpmax-eligible	0.0016%	62,456

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: C8G
Protein: p.Pro183Leu
Coding: c.548C>T
MANE Select: NM_000606
dbSNP: rs769430206
Type: single nucleotide variant
Location: chr9:136946558 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 15 PDB
Residue 183: a disulfide bond

Full C8G gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8G p.Tyr181His Uncertain significance ★★ ⚠ same type
C8G c.276-3C>T Likely benign ★★ same type
C8G p.Arg69Gln Benign ★★ same type
C8G p.Val196Ile Likely benign ★★ same type
C8G p.Ala128Thr Uncertain significance ★ ⚠ same type
C8G p.Ala136Thr Uncertain significance ★ ⚠ same type
C8G p.Ala143Val Uncertain significance ★ ⚠ same type
C8G p.Ala16Val 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/c8g-p-pro183leu (accessed [today's date]).

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