Is PBDC1 p.Leu22Pro (c.65T>C) pathogenic?

PBDC1 p.Leu22Pro (c.65T>C) is classified Uncertain significance in PBDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.954); Very rare (popmax 0.00599%, eas).

How common is PBDC1 p.Leu22Pro (c.65T>C) in the general population?

PBDC1 p.Leu22Pro (c.65T>C) is very rare (popmax 0.00599%, eas) (gnomAD).

What do computational predictors say about PBDC1 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely pathogenic (score 0.954) — an in-silico prediction, not a clinical call.

PBDC1 p.Leu22Pro

c.65T>C · VCV3414596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00599%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.954	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 1,759 bp · p 0.019 · regional, not allelic
Overall
CADD	23.0	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 0.00599% East Asian · 2/33,377 alleles

Filtering AF 0.000992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000371%

Overall 0.000167% 2/1,197,334 alleles · very rare exomes 2/1,084,038 · genomes 0/113,296 · joint denominator

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: PBDC1
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_016500
Type: single nucleotide variant
Location: chrX:76173619 (GRCh38)
Structure: AlphaFold pLDDT 76.66

Full PBDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PBDC1 p.Leu22Arg Likely benign ★ ⚠ same residue
PBDC1 p.Arg151Gln Uncertain significance ★ ⚠ same type
PBDC1 p.Asp212Glu Uncertain significance ★ ⚠ same type
PBDC1 p.Asp85Glu Uncertain significance ★ ⚠ same type
PBDC1 p.Glu131Gly Uncertain significance ★ same type
PBDC1 p.Glu192Asp Uncertain significance ★ ⚠ same type
PBDC1 p.Glu224Gln Uncertain significance ★ ⚠ same type
PBDC1 p.Glu80Asp 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/pbdc1-p-leu22pro (accessed [today's date]).

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