Is MAP4K4 p.Ala369Pro (c.1105G>C) pathogenic?

MAP4K4 p.Ala369Pro (c.1105G>C) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Ala369Pro (c.1105G>C)?

MAP4K4 p.Ala369Pro (c.1105G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Ala369Pro (c.1105G>C) in the general population?

MAP4K4 p.Ala369Pro (c.1105G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MAP4K4 p.Ala369Pro (c.1105G>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

MAP4K4 p.Ala369Pro

c.1105G>C · VCV4051461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 5% in MAP4K4
REVEL	0.249	benign-leaning
SaProt	LLR -13.20	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	27.1	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 8.48e-05% European (non-Finnish) · 1/1,178,556 alleles

Overall 6.21e-05% 1/1,611,008 alleles · very rare exomes 1/1,458,710 · genomes 0/152,298 · 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.Ala369Pro
Coding: c.1105G>C
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101844183 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB

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.Leu742Pro 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

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-ala369pro (accessed [today's date]).

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