Is PDF p.Pro136Leu (c.407C>T) pathogenic?

PDF p.Pro136Leu (c.407C>T) is classified Uncertain significance in PDF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.1156); Ultra-rare (popmax 0.0184%, eas).

How common is PDF p.Pro136Leu (c.407C>T) in the general population?

PDF p.Pro136Leu (c.407C>T) is ultra-rare (popmax 0.0184%, eas) (gnomAD).

What do computational predictors say about PDF p.Pro136Leu (c.407C>T)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

PDF p.Pro136Leu

c.407C>T · rs781757701 · VCV3210816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 1,545 bp · p 9e-06 · regional, not allelic
Overall
CADD	19.87	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 0.0184% East Asian · 7/37,990 alleles

Filtering AF 0.00863% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00609%

Overall 0.000653% 10/1,531,790 alleles · ultra-rare exomes 6/1,379,626 · genomes 4/152,164 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0184%	5,427
Remaining individualsnot grpmax-eligible	0.0017%	58,970
European (non-Finnish)	0.000175%	572,073

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.Pro136Leu
Coding: c.407C>T
MANE Select: NM_022341
dbSNP: rs781757701
Type: single nucleotide variant
Location: chr16:69330164 (GRCh38)
Gene constraint: LOEUF 1.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.21 · 2 PDB

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

Similar variants

COG8 c.*26+273T>C Benign ★★ same type
COG8 c.*330G>T Benign ★★ same type
COG8 c.*26+543C>T Uncertain significance ★ same type
COG8 c.*402A>G Uncertain significance ★ same type
COG8 c.*492C>T Uncertain significance ★ same type
COG8 c.*506C>T Uncertain significance ★ same type
COG8 c.*568G>T Uncertain significance ★ same type
PDF p.Pro73Ala Uncertain significance ★ ⚠ 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/pdf-p-pro136leu (accessed [today's date]).

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