Is PDF p.Pro149Leu (c.446C>T) pathogenic?

PDF p.Pro149Leu (c.446C>T) is classified Uncertain significance in PDF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.3363); Ultra-rare (popmax 0.0106%, amr).

How common is PDF p.Pro149Leu (c.446C>T) in the general population?

PDF p.Pro149Leu (c.446C>T) is ultra-rare (popmax 0.0106%, amr) (gnomAD).

What do computational predictors say about PDF p.Pro149Leu (c.446C>T)?

AlphaMissense predicts likely benign (score 0.3363) — an in-silico prediction, not a clinical call.

PDF p.Pro149Leu

c.446C>T · VCV4566354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3363 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.3363	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 1,545 bp · p 9e-06 · regional, not allelic
Overall
CADD	27.1	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 0.0106% Admixed American · 6/56,578 alleles

Filtering AF 0.0046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00254% 40/1,574,970 alleles · ultra-rare exomes 38/1,426,096 · genomes 2/148,874 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0106%	9,430
South Asian	0.00343%	29,179
African / African-American	0.00302%	33,129
European (non-Finnish)	0.0024%	41,663
Remaining individualsnot grpmax-eligible	0.00165%	60,774

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: PDF
Protein: p.Pro149Leu
Coding: c.446C>T
MANE Select: NM_022341
Type: single nucleotide variant
Location: chr16:69330125 (GRCh38)

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

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/pdf-p-pro149leu (accessed [today's date]).

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