Is C8G p.Arg142Pro (c.425G>C) pathogenic?

C8G p.Arg142Pro (c.425G>C) is classified Uncertain significance in C8G (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: ambiguous (0.5287); Very rare (popmax 0.00225%, eas).

How common is C8G p.Arg142Pro (c.425G>C) in the general population?

C8G p.Arg142Pro (c.425G>C) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about C8G p.Arg142Pro (c.425G>C)?

AlphaMissense predicts ambiguous (score 0.5287) — an in-silico prediction, not a clinical call.

C8G p.Arg142Pro

c.425G>C · VCV3826413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5287	ambiguous
REVEL	0.173	moderately benign-leaning
SaProt	LLR -14.11	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP 1.3
Regional constraint	o/e 1.12	unconstrained · MANE · 1,457 bp · p 0.046 · regional, not allelic
Overall
CADD	13.65	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 0.00225% East Asian · 1/44,406 alleles

Overall 0.000191% 3/1,567,624 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,406
African / African-American	0.00136%	73,486
European (non-Finnish)	8.66e-05%	1,155,172

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.Arg142Pro
Coding: c.425G>C
MANE Select: NM_000606
Type: single nucleotide variant
Location: chr9:136946163 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 15 PDB
Residue 142: a β-strand; 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-arg142pro (accessed [today's date]).

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