Is MAP2K5 p.Ala437Ser (c.1309G>T) pathogenic?

MAP2K5 p.Ala437Ser (c.1309G>T) is classified Uncertain significance in MAP2K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.00418%, nfe).

How common is MAP2K5 p.Ala437Ser (c.1309G>T) in the general population?

MAP2K5 p.Ala437Ser (c.1309G>T) is very rare (popmax 0.00418%, nfe) (gnomAD).

What do computational predictors say about MAP2K5 p.Ala437Ser (c.1309G>T)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

MAP2K5 p.Ala437Ser

c.1309G>T · VCV4103145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00418%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.25, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 100 bp · p 0.57 · regional, not allelic
Overall
CADD	16.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00418% European (non-Finnish) · 48/1,148,196 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00316% 49/1,552,186 alleles · very rare exomes 47/1,399,950 · genomes 2/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00418%	23,921
African / African-American	0.00137%	73,190

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: MAP2K5
Protein: p.Ala437Ser
Coding: c.1309G>T
MANE Select: NM_145160
Type: single nucleotide variant
Location: chr15:67806712 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.20 · 3 PDB

Full MAP2K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K5 c.586-8A>G Benign ★★ same type
MAP2K5 c.1074+1G>A Uncertain significance ★ same type
MAP2K5 p.Ala150Ser Uncertain significance ★ ⚠ same type
MAP2K5 p.Ala157Thr Uncertain significance ★ ⚠ same type
MAP2K5 p.Ala266Val Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Gln Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Trp Uncertain significance ★ same type
MAP2K5 p.Arg169Gln 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/map2k5-p-ala437ser (accessed [today's date]).

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