Is PASK p.Val213Ala (c.638T>C) pathogenic?

PASK p.Val213Ala (c.638T>C) is classified Uncertain significance in PASK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.4339); Ultra-rare (popmax 0.0164%, mid).

How common is PASK p.Val213Ala (c.638T>C) in the general population?

PASK p.Val213Ala (c.638T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PASK p.Val213Ala (c.638T>C)?

AlphaMissense predicts ambiguous (score 0.4339) — an in-silico prediction, not a clinical call.

PASK p.Val213Ala

c.638T>C · rs142624414 · VCV2360239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4339 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4339	ambiguous
REVEL	0.752	pathogenic-leaning
SaProt	LLR -8.95	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.68 · regional, not allelic
Overall
CADD	23.3	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00694% 112/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0154%	6,506
European (non-Finnish)	0.00542%	18,436

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val213Ala
Coding: c.638T>C
MANE Select: NM_015148
dbSNP: rs142624414
Type: single nucleotide variant
Location: chr2:241138757 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.14 · 2 PDB
Residue 213: a β-strand

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-val213ala (accessed [today's date]).

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