Is MGP p.Ser25Arg (c.75C>A) pathogenic?

MGP p.Ser25Arg (c.75C>A) is classified Uncertain significance in MGP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.9838); Ultra-rare (popmax 0.0342%, afr).

How common is MGP p.Ser25Arg (c.75C>A) in the general population?

MGP p.Ser25Arg (c.75C>A) is ultra-rare (popmax 0.0342%, afr) (gnomAD).

What do computational predictors say about MGP p.Ser25Arg (c.75C>A)?

AlphaMissense predicts likely pathogenic (score 0.9838) — an in-silico prediction, not a clinical call.

MGP p.Ser25Arg

c.75C>A · rs755306746 · VCV1979715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9838 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9838	likely pathogenic · top 3% in MGP
REVEL	0.395	indeterminate
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 3,649 bp · p 0.62 · regional, not allelic
Overall
CADD	24.9	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 0.0342% African / African-American · 24/70,130 alleles

Filtering AF 0.0236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.00187% 27/1,443,932 alleles · ultra-rare exomes 11/1,295,160 · genomes 16/148,772 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0342%	2,922
Admixed American	0.00364%	27,482
Remaining individualsnot grpmax-eligible	0.0018%	55,684

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: MGP
Protein: p.Ser25Arg
Coding: c.75C>A
MANE Select: NM_000900
dbSNP: rs755306746
Type: single nucleotide variant
Location: chr12:14884232 (GRCh38)
Gene constraint: LOEUF 1.63 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 3 PDB
Residue 25: a modified residue (phosphoserine)

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

Similar variants

MGP c.94+1G>A Pathogenic/Likely pathogenic ★★ same type
MGP c.94+5G>A Uncertain significance ★★ same type
MGP p.Arg61His Uncertain significance ★★ ⚠ same type
MGP p.Gln47Glu Uncertain significance ★★ ⚠ same type
MGP p.Met26Thr Uncertain significance ★★ ⚠ same type
MGP p.Tyr76His Uncertain significance ★★ ⚠ same type
MGP c.171-67T>A Likely benign ★★ same type
MGP c.61+10T>G Likely benign ★★ 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/mgp-p-ser25arg (accessed [today's date]).

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