Is MAP4K4 p.Ala491Pro (c.1471G>C) pathogenic?

MAP4K4 p.Ala491Pro (c.1471G>C) is classified Uncertain significance in MAP4K4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Ala491Pro (c.1471G>C)?

MAP4K4 p.Ala491Pro (c.1471G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Ala491Pro (c.1471G>C) in the general population?

MAP4K4 p.Ala491Pro (c.1471G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP4K4 p.Ala491Pro (c.1471G>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

MAP4K4 p.Ala491Pro

c.1471G>C · VCV4103554

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 7% in MAP4K4
REVEL	0.363	indeterminate
SaProt	LLR -16.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1e-07 · regional, not allelic
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP4K4
Protein: p.Ala491Pro
Coding: c.1471G>C
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101859071 (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.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
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-ala491pro (accessed [today's date]).

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