Is PGD p.Ser140Leu (c.419C>T) pathogenic?

PGD p.Ser140Leu (c.419C>T) is classified Uncertain significance in PGD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: likely pathogenic (0.9682); Very rare (popmax 0.000679%, nfe).

How common is PGD p.Ser140Leu (c.419C>T) in the general population?

PGD p.Ser140Leu (c.419C>T) is very rare (popmax 0.000679%, nfe) (gnomAD).

What do computational predictors say about PGD p.Ser140Leu (c.419C>T)?

AlphaMissense predicts likely pathogenic (score 0.9682) — an in-silico prediction, not a clinical call.

PGD p.Ser140Leu

c.419C>T · rs768286066 · VCV2334063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000679%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9682	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -15.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 20 kb · p 1e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000679% European (non-Finnish) · 8/1,178,968 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,612,572 alleles · very rare exomes 6/1,460,446 · genomes 2/152,126 · 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: PGD
Protein: p.Ser140Leu
Coding: c.419C>T
MANE Select: NM_002631
dbSNP: rs768286066
Type: single nucleotide variant
Location: chr1:10404249 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 96.98 · 4 PDB
Residue 140: a β-strand

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

Similar variants

PGD c.519+2C>T Uncertain significance ★ same type
PGD p.Ala149Gly Uncertain significance ★ ⚠ same type
PGD p.Ala258Val Uncertain significance ★ ⚠ same type
PGD p.Ala336Pro Uncertain significance ★ ⚠ same type
PGD p.Ala345Gly Uncertain significance ★ ⚠ same type
PGD p.Arg407Gln Uncertain significance ★ ⚠ same type
PGD p.Asn354Ser Uncertain significance ★ ⚠ same type
PGD p.Asn354Tyr 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/pgd-p-ser140leu (accessed [today's date]).

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