Is MAP2K5 p.Phe346Ser (c.1037T>C) pathogenic?

MAP2K5 p.Phe346Ser (c.1037T>C) is classified Uncertain significance in MAP2K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.9612); Absent from gnomAD v4.1.

How common is MAP2K5 p.Phe346Ser (c.1037T>C) in the general population?

MAP2K5 p.Phe346Ser (c.1037T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K5 p.Phe346Ser (c.1037T>C)?

AlphaMissense predicts likely pathogenic (score 0.9612) — an in-silico prediction, not a clinical call.

MAP2K5 p.Phe346Ser

c.1037T>C · rs540623937 · VCV2535958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9612 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9612	likely pathogenic
REVEL	0.513	indeterminate
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 160 kb · p 4.7e-09 · regional, not allelic
Overall
CADD	26.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP2K5
Protein: p.Phe346Ser
Coding: c.1037T>C
MANE Select: NM_145160
dbSNP: rs540623937
Type: single nucleotide variant
Location: chr15:67703401 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.20 · 3 PDB
Residue 346: the protein kinase domain

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.Ala437Ser Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Gln Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Trp 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-phe346ser (accessed [today's date]).

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