Is MAP4K4 p.Leu742Pro (c.2225T>C) pathogenic?

MAP4K4 p.Leu742Pro (c.2225T>C) is classified Uncertain significance in MAP4K4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-27). AlphaMissense: likely pathogenic (0.9361); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Leu742Pro (c.2225T>C)?

MAP4K4 p.Leu742Pro (c.2225T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Leu742Pro (c.2225T>C) in the general population?

MAP4K4 p.Leu742Pro (c.2225T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MAP4K4 p.Leu742Pro (c.2225T>C)?

AlphaMissense predicts likely pathogenic (score 0.9361) — an in-silico prediction, not a clinical call.

MAP4K4 p.Leu742Pro

c.2225T>C · VCV4051465

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9361	likely pathogenic
REVEL	0.213	benign-leaning
SaProt	LLR -4.90	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 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1e-07 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L664P vs ClinVar L742P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,374 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,348 alleles · very rare exomes 4/1,461,134 · genomes 0/152,214 · joint denominator

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: MAP4K4
Protein: p.Leu742Pro
Coding: c.2225T>C
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101866448 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 664 UniProt numbering: the 'disordered' region

Full MAP4K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP4K4 p.Arg1329Ter Pathogenic/Likely pathogenic ★★ same condition
MAP4K4 p.Ala491Pro Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Asp203Gly Likely pathogenic ★ same condition
MAP4K4 p.Gln402Ter Pathogenic ★ same condition
MAP4K4 p.Gly173Asp Pathogenic ★ same condition
MAP4K4 p.Lys54Arg Likely pathogenic ★ same condition
MAP4K4 p.Tyr210Cys Pathogenic ★ 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/map4k4-p-leu742pro (accessed [today's date]).

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