Is PRDM9 p.Arg755Pro (c.2264G>C) pathogenic?

PRDM9 p.Arg755Pro (c.2264G>C) is classified Uncertain significance in PRDM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely pathogenic (0.8972); Very rare (popmax 0.00209%, afr).

How common is PRDM9 p.Arg755Pro (c.2264G>C) in the general population?

PRDM9 p.Arg755Pro (c.2264G>C) is very rare (popmax 0.00209%, afr) (gnomAD).

What do computational predictors say about PRDM9 p.Arg755Pro (c.2264G>C)?

AlphaMissense predicts likely pathogenic (score 0.8972) — an in-silico prediction, not a clinical call.

PRDM9 p.Arg755Pro

c.2264G>C · rs749735500 · VCV2249964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00209%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8972	likely pathogenic · top 9% in PRDM9
REVEL	0.109	moderately benign-leaning
SaProt	LLR -16.59	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.2
Regional constraint	o/e 0.50	unconstrained · MANE · 567 bp · p 6.1e-12 · regional, not allelic
Overall
CADD	21.5	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 0.00209% African / African-American · 1/47,756 alleles

Filtering AF 0.000556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000439%

Overall 0.000914% 14/1,531,698 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00209%	47,756
Remaining individualsnot grpmax-eligible	0.00166%	60,210
European (non-Finnish)	0.00104%	95,902

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: PRDM9
Protein: p.Arg755Pro
Coding: c.2264G>C
MANE Select: NM_020227
dbSNP: rs749735500
Type: single nucleotide variant
Location: chr5:23527352 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.19 · 5 PDB
Residue 755: the 'dna-binding' region

Full PRDM9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRDM9 c.301+67A>G Benign ★★ same type
PRDM9 c.509-41C>T Benign ★★ same type
PRDM9 c.883-52C>T Benign ★★ same type
PRDM9 c.*125G>A Benign ★★ same type
PRDM9 c.*37A>G Benign ★★ same type
PRDM9 p.Asn790His Likely benign ★★ same type
PRDM9 p.Asp30= Benign ★★ same type
PRDM9 p.Gly144= 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/prdm9-p-arg755pro (accessed [today's date]).

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