Is PRMT8 p.Pro33His (c.98C>A) pathogenic?

PRMT8 p.Pro33His (c.98C>A) is classified Uncertain significance in PRMT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0457%, sas).

How common is PRMT8 p.Pro33His (c.98C>A) in the general population?

PRMT8 p.Pro33His (c.98C>A) is ultra-rare (popmax 0.0457%, sas) (gnomAD).

What do computational predictors say about PRMT8 p.Pro33His (c.98C>A)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

PRMT8 p.Pro33His

c.98C>A · VCV4144686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0457%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 82 bp · p 0.063 · regional, not allelic
Overall
CADD	21.9	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 0.0457% South Asian · 40/87,568 alleles

Filtering AF 0.0344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0305%

Overall 0.00693% 103/1,486,012 alleles · ultra-rare exomes 89/1,334,384 · genomes 14/151,628 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0457%	2,189
Middle Eastern	0.0172%	5,816
East Asian	0.00679%	14,731
African / African-American	0.00556%	17,990
European (non-Finnish)	0.00486%	20,558
Remaining individualsnot grpmax-eligible	0.00343%	29,144
Admixed American	0.00177%	56,442

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: PRMT8
Protein: p.Pro33His
Coding: c.98C>A
MANE Select: NM_019854
Type: single nucleotide variant
Location: chr12:3540628 (GRCh38)
Gene constraint: LOEUF 0.293 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.66 · 2 PDB
Residue 33: the 'disordered' region

Full PRMT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRMT8 p.Pro33Arg Uncertain significance ★ ⚠ same residue
PRMT8 p.Pro33Ser Uncertain significance ★ ⚠ same residue
PRMT8 p.Asp78= Benign ★★ same type
PRMT8 p.Ala17Glu Uncertain significance ★ ⚠ same type
PRMT8 p.Ala17Thr Uncertain significance ★ ⚠ same type
PRMT8 p.Ala306Thr Uncertain significance ★ ⚠ same type
PRMT8 p.Arg251Trp Uncertain significance ★ ⚠ same type
PRMT8 p.Arg300Cys 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/prmt8-p-pro33his (accessed [today's date]).

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