Is PRDM9 p.Arg447Cys (c.1339C>T) pathogenic?

PRDM9 p.Arg447Cys (c.1339C>T) is classified Likely benign in PRDM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0468%, eas).

How common is PRDM9 p.Arg447Cys (c.1339C>T) in the general population?

PRDM9 p.Arg447Cys (c.1339C>T) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about PRDM9 p.Arg447Cys (c.1339C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

PRDM9 p.Arg447Cys

c.1339C>T · rs769065945 · VCV2387520

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -7.31	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 -6.6	GERP -3.7
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.061 · regional, not allelic
Overall
CADD	4.918	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 0.0468% East Asian · 21/44,868 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00359% 58/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,137
Admixed American	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.0011%	90,771

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.Arg447Cys
Coding: c.1339C>T
MANE Select: NM_020227
dbSNP: rs769065945
Type: single nucleotide variant
Location: chr5:23526427 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.19 · 5 PDB
Residue 447: the 'disordered' 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-arg447cys (accessed [today's date]).

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