Is PASK p.Leu167Phe (c.499C>T) pathogenic?

PASK p.Leu167Phe (c.499C>T) is classified Uncertain significance in PASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: ambiguous (0.3588); Very rare (popmax 0.005%, amr).

How common is PASK p.Leu167Phe (c.499C>T) in the general population?

PASK p.Leu167Phe (c.499C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PASK p.Leu167Phe (c.499C>T)?

AlphaMissense predicts ambiguous (score 0.3588) — an in-silico prediction, not a clinical call.

PASK p.Leu167Phe

c.499C>T · rs200237047 · VCV3208920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
AlphaMissense	0.3588	ambiguous
REVEL	0.593	indeterminate
SaProt	LLR -5.28	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.68 · regional, not allelic
Overall
CADD	23.7	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 0.005% Admixed American · 3/60,032 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,674 alleles · very rare

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: PASK
Protein: p.Leu167Phe
Coding: c.499C>T
MANE Select: NM_015148
dbSNP: rs200237047
Type: single nucleotide variant
Location: chr2:241139986 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.14 · 2 PDB
Residue 167: the pas 1 domain; an α-helix

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

Similar variants

PASK c.3533+1G>A Uncertain significance ★★ same type
PASK p.Arg1319His Benign ★★ same type
PASK p.Arg937His Benign ★★ same type
PASK p.Gly782Arg Benign ★★ same type
PASK p.Pro101= Benign ★★ same type
PASK p.Pro844= Benign ★★ same type
PASK p.Ser582= Benign ★★ same type
PASK p.Ser789= Benign ★★ 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/pask-p-leu167phe (accessed [today's date]).

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