Is PGD p.Leu458Phe (c.1374G>T) pathogenic?

PGD p.Leu458Phe (c.1374G>T) is classified Uncertain significance in PGD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-04). AlphaMissense: likely benign (0.2124); Very rare (popmax 0.00329%, sas).

How common is PGD p.Leu458Phe (c.1374G>T) in the general population?

PGD p.Leu458Phe (c.1374G>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about PGD p.Leu458Phe (c.1374G>T)?

AlphaMissense predicts likely benign (score 0.2124) — an in-silico prediction, not a clinical call.

PGD p.Leu458Phe

c.1374G>T · rs1450469652 · VCV2532497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2124	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.001	GERP -4.4
Regional constraint	o/e 1.09	unconstrained · MANE · 97 bp · p 0.55 · regional, not allelic
Overall
CADD	21.6	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 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,614,138 alleles · very rare exomes 3/1,461,886 · genomes 0/152,252 · 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.Leu458Phe
Coding: c.1374G>T
MANE Select: NM_002631
dbSNP: rs1450469652
Type: single nucleotide variant
Location: chr1:10419671 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 96.98 · 4 PDB

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-leu458phe (accessed [today's date]).

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