Is PDYN p.Pro244Leu (c.731C>T) pathogenic?

PDYN p.Pro244Leu (c.731C>T) is classified Uncertain significance in PDYN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.369); Ultra-rare (popmax 0.0362%, sas); Associated with Inborn genetic diseases.

What condition is associated with PDYN p.Pro244Leu (c.731C>T)?

PDYN p.Pro244Leu (c.731C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDYN p.Pro244Leu (c.731C>T) in the general population?

PDYN p.Pro244Leu (c.731C>T) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about PDYN p.Pro244Leu (c.731C>T)?

AlphaMissense predicts ambiguous (score 0.369) — an in-silico prediction, not a clinical call.

PDYN p.Pro244Leu

c.731C>T · rs765854641 · VCV1366955

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.369	ambiguous
REVEL	0.651	pathogenic-leaning
SaProt	LLR -6.05	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,758 bp · p 0.27 · regional, not allelic
Overall
CADD	28.7	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 0.0362% South Asian · 33/91,076 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00304% 49/1,613,982 alleles · ultra-rare exomes 47/1,461,888 · genomes 2/152,094 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,760
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00333%	30,001
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)	0.000678%	147,505

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: PDYN
Protein: p.Pro244Leu
Coding: c.731C>T
MANE Select: NM_024411
dbSNP: rs765854641
Type: single nucleotide variant
Location: chr20:1980357 (GRCh38)
Gene constraint: LOEUF 0.769 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 8 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDYN p.Pro244= Benign ★ same residue
PDYN p.Ala190Ser Uncertain significance ★★ ⚠ same condition
PDYN p.Ala20Val Uncertain significance ★★ ⚠ same condition
PDYN p.Arg180Ser Uncertain significance ★★ ⚠ same condition
PDYN p.Arg231Trp Uncertain significance ★★ ⚠ same condition
PDYN p.Cys45Trp Uncertain significance ★★ ⚠ same condition
PDYN p.Glu242Lys Uncertain significance ★★ ⚠ same condition
PDYN p.Gly191Trp Uncertain significance ★★ ⚠ 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/pdyn-p-pro244leu (accessed [today's date]).

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