Is MAP3K3 p.Thr438Ser (c.1313C>G) pathogenic?

MAP3K3 p.Thr438Ser (c.1313C>G) is classified Uncertain significance in MAP3K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely benign (0.2037); Rare (popmax 0.194%, afr); Associated with cerebral cavernous malformations 5.

What condition is associated with MAP3K3 p.Thr438Ser (c.1313C>G)?

MAP3K3 p.Thr438Ser (c.1313C>G) is associated with cerebral cavernous malformations 5 (ClinVar).

How common is MAP3K3 p.Thr438Ser (c.1313C>G) in the general population?

MAP3K3 p.Thr438Ser (c.1313C>G) is rare (popmax 0.194%, afr) (gnomAD).

What do computational predictors say about MAP3K3 p.Thr438Ser (c.1313C>G)?

AlphaMissense predicts likely benign (score 0.2037) — an in-silico prediction, not a clinical call.

MAP3K3 p.Thr438Ser

c.1313C>G · VCV3600420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2037 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.194%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformations 5

Computational evidence

Protein change
AlphaMissense	0.2037	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.97	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 4.1	GERP 0.54, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 12 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	23.2	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 0.194% African / African-American · 146/75,076 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.0107% 172/1,614,190 alleles · rare exomes 83/1,461,820 · genomes 89/152,370 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.194%	514
Admixed American	0.0383%	2,610
Remaining individualsnot grpmax-eligible	0.0048%	20,837

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: MAP3K3
Protein: p.Thr438Ser
Coding: c.1313C>G
MANE Select: NM_002401
Type: single nucleotide variant
Location: chr17:63691202 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 6 PDB
Residue 438: the protein kinase domain

Full MAP3K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral cavernous malformations 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K3 p.Thr438Asn Uncertain significance ★ ⚠ same residue
MAP3K3 p.His133Tyr Uncertain significance ★★ ⚠ same condition
MAP3K3 p.Met524Val Uncertain significance ★★ ⚠ same condition
MAP3K3 p.Arg313Cys Uncertain significance ★ same condition
MAP3K3 p.Gln392His Uncertain significance ★ ⚠ same condition
MAP3K3 p.Lys391Arg Uncertain significance ★ ⚠ same condition
MAP3K3 p.Met31Val Uncertain significance ★ ⚠ same condition
MAP3K3 p.Val64Met Uncertain significance ★ ⚠ same condition

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/map3k3-p-thr438ser (accessed [today's date]).

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