Is MAP4K5 p.Ile452Val (c.1354A>G) pathogenic?

MAP4K5 p.Ile452Val (c.1354A>G) is classified Uncertain significance in MAP4K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). AlphaMissense: likely benign (0.0648); Rare (popmax 0.198%, mid).

How common is MAP4K5 p.Ile452Val (c.1354A>G) in the general population?

MAP4K5 p.Ile452Val (c.1354A>G) is rare (popmax 0.198%, mid) (gnomAD).

What do computational predictors say about MAP4K5 p.Ile452Val (c.1354A>G)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

MAP4K5 p.Ile452Val

c.1354A>G · rs373537452 · VCV2644227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.1, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 0.0017 · regional, not allelic
Overall
CADD	13.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.198% Middle Eastern · 12/6,046 alleles

Filtering AF 0.134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.0178% 285/1,601,618 alleles · rare exomes 263/1,449,260 · genomes 22/152,358 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	504
South Asian	0.155%	646
Remaining individualsnot grpmax-eligible	0.0209%	4,776
European (non-Finnish)	0.00955%	10,471
African / African-American	0.008%	12,494
East Asian	0.00448%	22,313
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,370
Admixed American	0.00171%	58,368

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: MAP4K5
Protein: p.Ile452Val
Coding: c.1354A>G
MANE Select: NM_006575
dbSNP: rs373537452
Type: single nucleotide variant
Location: chr14:50444022 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.15
Residue 452: the 'disordered' region

Full MAP4K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K5 p.Val739Ile Uncertain significance ★★ ⚠ same type
ATL1 c.-140+55A>T Benign ★★ same type
MAP4K5 p.Val731= Benign ★★ same type
MAP4K5 c.1709-2A>T Uncertain significance ★ same type
MAP4K5 p.Ala278Thr Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala328Val Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala37Val Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala425Thr 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/map4k5-p-ile452val (accessed [today's date]).

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