Is MAP4K3 p.Leu403Phe (c.1209G>C) pathogenic?

MAP4K3 p.Leu403Phe (c.1209G>C) is classified Uncertain significance in MAP4K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9878); Very rare (popmax 0.00195%, amr).

How common is MAP4K3 p.Leu403Phe (c.1209G>C) in the general population?

MAP4K3 p.Leu403Phe (c.1209G>C) is very rare (popmax 0.00195%, amr) (gnomAD).

What do computational predictors say about MAP4K3 p.Leu403Phe (c.1209G>C)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

MAP4K3 p.Leu403Phe

c.1209G>C · VCV4549582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -3.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 76 kb · p 0.027 · regional, not allelic
Overall
CADD	16.84	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 0.00195% Admixed American · 1/51,340 alleles

Overall 0.000129% 2/1,549,180 alleles · very rare exomes 1/1,397,092 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00195%	51,340
European (non-Finnish)	8.74e-05%	1,144,163

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: MAP4K3
Protein: p.Leu403Phe
Coding: c.1209G>C
MANE Select: NM_003618
Type: single nucleotide variant
Location: chr2:39293238 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.96 · 1 PDB

Full MAP4K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K3 p.Ala253Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala310Val Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala391Glu Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala429Val Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala621Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala664Pro Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala75Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Arg482Lys 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/map4k3-p-leu403phe (accessed [today's date]).

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