Is MAP3K3 p.Arg241Trp (c.721C>T) pathogenic?

MAP3K3 p.Arg241Trp (c.721C>T) is classified Uncertain significance in MAP3K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1817); Ultra-rare (popmax 0.033%, mid).

How common is MAP3K3 p.Arg241Trp (c.721C>T) in the general population?

MAP3K3 p.Arg241Trp (c.721C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about MAP3K3 p.Arg241Trp (c.721C>T)?

AlphaMissense predicts likely benign (score 0.1817) — an in-silico prediction, not a clinical call.

MAP3K3 p.Arg241Trp

c.721C>T · VCV4103330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1817 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1817	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.23	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 2.9	GERP 0.58, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 12 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	26.7	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00273% 44/1,614,048 alleles · ultra-rare exomes 41/1,461,794 · genomes 3/152,254 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.00549%	18,216
European (non-Finnish)	0.00288%	34,704
East Asian	0.00223%	44,888
Admixed American	0.00167%	60,018
African / African-American	0.00133%	75,000

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.Arg241Trp
Coding: c.721C>T
MANE Select: NM_002401
Type: single nucleotide variant
Location: chr17:63688537 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 6 PDB
Residue 241: the 'disordered' region

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

Similar variants

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MAP3K3 p.His133Tyr Uncertain significance ★★ ⚠ same type
MAP3K3 p.Met524Val Uncertain significance ★★ ⚠ same type
MAP3K3 c.126+67G>T Benign ★★ same type
MAP3K3 c.1475-146T>C Benign ★★ same type
MAP3K3 c.168-35A>G Benign ★★ same type
MAP3K3 c.268-98T>C Benign ★★ same type
MAP3K3 c.382-260A>G 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/map3k3-p-arg241trp (accessed [today's date]).

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