Is MAP4K4 p.Arg371Trp (c.1111C>T) pathogenic?

MAP4K4 p.Arg371Trp (c.1111C>T) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9025); Very rare (popmax 0.00168%, amr); Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Arg371Trp (c.1111C>T)?

MAP4K4 p.Arg371Trp (c.1111C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Arg371Trp (c.1111C>T) in the general population?

MAP4K4 p.Arg371Trp (c.1111C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about MAP4K4 p.Arg371Trp (c.1111C>T)?

AlphaMissense predicts likely pathogenic (score 0.9025) — an in-silico prediction, not a clinical call.

MAP4K4 p.Arg371Trp

c.1111C>T · rs1191731616 · VCV3123112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9025 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9025	likely pathogenic
REVEL	0.309	indeterminate
SaProt	LLR -14.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.35, phastCons 0.98
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00168% Admixed American · 1/59,510 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.00112% 18/1,610,110 alleles · very rare exomes 16/1,458,020 · genomes 2/152,090 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,510
European (non-Finnish)	0.00144%	69,307

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.Arg371Trp
Coding: c.1111C>T
MANE Select: NM_001395002
dbSNP: rs1191731616
Type: single nucleotide variant
Location: chr2:101844189 (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

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MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Asp203Gly Likely pathogenic ★ same condition
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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-arg371trp (accessed [today's date]).

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