Is MAP2K3 p.Asp208Val (c.623A>T) pathogenic?

MAP2K3 p.Asp208Val (c.623A>T) is classified Likely benign in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-14). AlphaMissense: likely pathogenic (1); Rare (popmax 0.75%, mid).

How common is MAP2K3 p.Asp208Val (c.623A>T) in the general population?

MAP2K3 p.Asp208Val (c.623A>T) is rare (popmax 0.75%, mid) (gnomAD).

What do computational predictors say about MAP2K3 p.Asp208Val (c.623A>T)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

MAP2K3 p.Asp208Val

c.623A>T · rs138917253 · VCV719739

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.75%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 3% in MAP2K3
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -12.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 71 bp · p 0.00056 · regional, not allelic
Overall
CADD	27.8	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 0.75% Middle Eastern · 45/6,000 alleles

Filtering AF 0.576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.515%

Overall 0.0597% 962/1,612,396 alleles · rare exomes 845/1,460,016 · genomes 117/152,380 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.75%	133
South Asian	0.466%	215
Ashkenazi Jewishnot grpmax-eligible	0.446%	224
Remaining individualsnot grpmax-eligible	0.127%	790
Admixed American	0.085%	1,176
European (non-Finnish)	0.02%	4,999
African / African-American	0.00133%	75,088

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: MAP2K3
Protein: p.Asp208Val
Coding: c.623A>T
MANE Select: NM_145109
dbSNP: rs138917253
Type: single nucleotide variant
Location: chr17:21304480 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 208: the protein kinase domain

Full MAP2K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same type
MAP2K3 c.568+10C>T Benign ★★ same type
MAP2K3 p.Ala220= Benign ★★ same type
MAP2K3 p.Ala225= Likely benign ★★ same type
MAP2K3 p.Leu25= Benign ★★ same type
MAP2K3 p.Leu319= Likely benign ★★ same type
MAP2K3 p.Pro40Thr Benign ★★ same type
MAP2K3 p.Ser286= Likely 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/map2k3-p-asp208val (accessed [today's date]).

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