Is MAP4K4 p.Phe172Ile (c.514T>A) pathogenic?

MAP4K4 p.Phe172Ile (c.514T>A) is classified Likely pathogenic in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with MAP4K4-related neurodevelopmental delay.

What condition is associated with MAP4K4 p.Phe172Ile (c.514T>A)?

MAP4K4 p.Phe172Ile (c.514T>A) is associated with MAP4K4-related neurodevelopmental delay (ClinVar).

How common is MAP4K4 p.Phe172Ile (c.514T>A) in the general population?

MAP4K4 p.Phe172Ile (c.514T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP4K4 p.Phe172Ile (c.514T>A)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

MAP4K4 p.Phe172Ile

c.514T>A · VCV3374718

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAP4K4-related neurodevelopmental delay

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic ✓ concordant with ClinVar · top 5% in MAP4K4
REVEL	0.77	pathogenic-leaning
SaProt	LLR -14.31	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 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	26.7	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

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.Phe172Ile
Coding: c.514T>A
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101831726 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 172: the protein kinase domain

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

Disease context

MAP4K4-related neurodevelopmental delay

Similar variants

MAP4K4 p.Arg152Gln Likely pathogenic ★ same condition
MAP4K4 p.Arg1228Lys Uncertain significance ★ ⚠ same condition
MAP4K4 p.Thr1054Ser Uncertain significance ★ ⚠ same condition
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

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-phe172ile (accessed [today's date]).

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