Is C8G p.Arg25Ser (c.75G>T) pathogenic?

C8G p.Arg25Ser (c.75G>T) is classified Uncertain significance in C8G (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.2336); Ultra-rare (popmax 0.0347%, afr).

How common is C8G p.Arg25Ser (c.75G>T) in the general population?

C8G p.Arg25Ser (c.75G>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about C8G p.Arg25Ser (c.75G>T)?

AlphaMissense predicts likely benign (score 0.2336) — an in-silico prediction, not a clinical call.

C8G p.Arg25Ser

c.75G>T · rs148013051 · VCV2212570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2336 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2336	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -2.8, phastCons 0.001
Regional constraint	o/e 1.12	unconstrained · MANE · 1,457 bp · p 0.046 · regional, not allelic
Overall
CADD	12.98	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 0.0347% African / African-American · 26/74,888 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.0018% 29/1,609,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,880
Admixed American	0.00168%	59,398
South Asian	0.00111%	90,312
European (non-Finnish)	8.48e-05%	1,178,616

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.Arg25Ser
Coding: c.75G>T
MANE Select: NM_000606
dbSNP: rs148013051
Type: single nucleotide variant
Location: chr9:136945395 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 15 PDB

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-arg25ser (accessed [today's date]).

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