Is PRDM5 p.Arg261Ser (c.783G>T) pathogenic?

PRDM5 p.Arg261Ser (c.783G>T) is classified Uncertain significance in PRDM5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-29). AlphaMissense: ambiguous (0.3852); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with PRDM5 p.Arg261Ser (c.783G>T)?

PRDM5 p.Arg261Ser (c.783G>T) is associated with Cardiovascular phenotype, brittle cornea syndrome 2 (ClinVar).

How common is PRDM5 p.Arg261Ser (c.783G>T) in the general population?

PRDM5 p.Arg261Ser (c.783G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PRDM5 p.Arg261Ser (c.783G>T)?

AlphaMissense predicts ambiguous (score 0.3852) — an in-silico prediction, not a clinical call.

PRDM5 p.Arg261Ser

c.783G>T · rs1396791897 · VCV1760857

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3852	ambiguous
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.44, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 145 kb · p 0.23 · regional, not allelic
Overall
CADD	23.2	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 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000372% 6/1,614,136 alleles · very rare exomes 6/1,461,840 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Admixed Americangrpmax	0.00167%	59,990
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)	0.000169%	590,019

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PRDM5
Protein: p.Arg261Ser
Coding: c.783G>T
MANE Select: NM_018699
dbSNP: rs1396791897
Type: single nucleotide variant
Location: chr4:120816535 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.53 · 1 PDB

Full PRDM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brittle cornea syndrome 2

Similar variants

PRDM5 p.Arg261Thr Uncertain significance ★ ⚠ same residue
PRDM5 c.1623+1G>A Likely pathogenic ★★ same condition
PRDM5 c.865+1G>A Likely pathogenic ★★ same condition
PRDM5 p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Arg346Ter Pathogenic ★★ same condition
PRDM5 p.Gln420Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Gln556Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Glu103Ter Pathogenic/Likely pathogenic ★★ same condition

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/prdm5-p-arg261ser (accessed [today's date]).

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