Is MAP3K5 p.Ala283Val (c.848C>T) pathogenic?

MAP3K5 p.Ala283Val (c.848C>T) is classified Uncertain significance in MAP3K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.6864); Very rare (popmax 0.000424%, nfe).

How common is MAP3K5 p.Ala283Val (c.848C>T) in the general population?

MAP3K5 p.Ala283Val (c.848C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MAP3K5 p.Ala283Val (c.848C>T)?

AlphaMissense predicts likely pathogenic (score 0.6864) — an in-silico prediction, not a clinical call.

MAP3K5 p.Ala283Val

c.848C>T · VCV4549476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6864	likely pathogenic
REVEL	0.361	indeterminate
SaProt	LLR -10.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 169 kb · p 9.4e-10 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,179,640 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,480 alleles · very rare exomes 6/1,461,200 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)grpmax	0.000424%	235,928

Remaining individuals 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: MAP3K5
Protein: p.Ala283Val
Coding: c.848C>T
MANE Select: NM_005923
Type: single nucleotide variant
Location: chr6:136697346 (GRCh38)
Gene constraint: LOEUF 0.433 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.87 · 27 PDB
Residue 283: an α-helix

Full MAP3K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K5 p.Ala1162Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala1166Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala1322Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala422Pro Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala909Thr Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1014Gln Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1239Trp Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1272Gly 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/map3k5-p-ala283val (accessed [today's date]).

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