Is MAP4K4 p.Phe265Ser (c.794T>C) pathogenic?

MAP4K4 p.Phe265Ser (c.794T>C) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1.

How common is MAP4K4 p.Phe265Ser (c.794T>C) in the general population?

MAP4K4 p.Phe265Ser (c.794T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP4K4 p.Phe265Ser (c.794T>C)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

MAP4K4 p.Phe265Ser

c.794T>C · VCV4528229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic · top 5% in MAP4K4
REVEL	0.731	pathogenic-leaning
SaProt	LLR -16.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	27.9	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

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.Phe265Ser
Coding: c.794T>C
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101839839 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 265: the protein kinase domain; an α-helix

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

Similar variants

MAP4K4 p.Arg1329Ter Pathogenic/Likely pathogenic ★★ same type
MAP4K4 p.Ala491Pro Uncertain significance ★★ ⚠ same type
MAP4K4 p.Arg1135Cys Uncertain significance ★★ ⚠ same type
MAP4K4 p.Leu742Pro Uncertain significance ★★ ⚠ same type
MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same type
MAP4K4 c.1022+125A>G Benign ★★ same type
MAP4K4 c.123+57A>G Benign ★★ same type
MAP4K4 c.1234-81C>G Benign ★★ 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/map4k4-p-phe265ser (accessed [today's date]).

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