Is CARM1 p.Pro25Arg (c.74C>G) pathogenic?

CARM1 p.Pro25Arg (c.74C>G) is classified Uncertain significance in CARM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely benign (0.1554); Very rare (popmax 0.00336%, sas).

How common is CARM1 p.Pro25Arg (c.74C>G) in the general population?

CARM1 p.Pro25Arg (c.74C>G) is very rare (popmax 0.00336%, sas) (gnomAD).

What do computational predictors say about CARM1 p.Pro25Arg (c.74C>G)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

CARM1 p.Pro25Arg

c.74C>G · VCV3827427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.41	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 6.7	GERP 0.62, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 36 kb · p 9e-05 · regional, not allelic
Overall
CADD	21.6	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 0.00336% South Asian · 1/29,786 alleles

Filtering AF 0.000536% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00039%

Overall 0.00112% 13/1,165,556 alleles · very rare exomes 12/1,016,932 · genomes 1/148,624 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00336%	29,786
Remaining individualsnot grpmax-eligible	0.00249%	40,232
African / African-American	0.00164%	61,098
European (non-Finnish)	0.00106%	94,414

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: CARM1
Protein: p.Pro25Arg
Coding: c.74C>G
MANE Select: NM_199141
Type: single nucleotide variant
Location: chr19:10871776 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.20 · 33 PDB

Full CARM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARM1 p.Pro25Leu Uncertain significance ★ ⚠ same residue
CARM1 p.Val226= Benign ★★ same type
CARM1 p.Ala15Val Uncertain significance ★ ⚠ same type
CARM1 p.Ala202Ser Uncertain significance ★ ⚠ same type
CARM1 p.Ala212Thr Uncertain significance ★ ⚠ same type
CARM1 p.Ala428Thr Uncertain significance ★ ⚠ same type
CARM1 p.Ala525Val Uncertain significance ★ ⚠ same type
CARM1 p.Ala55Glu 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/carm1-p-pro25arg (accessed [today's date]).

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