Is MAP4K5 p.Pro7Leu (c.20C>T) pathogenic?

MAP4K5 p.Pro7Leu (c.20C>T) is classified Uncertain significance in MAP4K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.154); Ultra-rare (popmax 0.0142%, amr).

How common is MAP4K5 p.Pro7Leu (c.20C>T) in the general population?

MAP4K5 p.Pro7Leu (c.20C>T) is ultra-rare (popmax 0.0142%, amr) (gnomAD).

What do computational predictors say about MAP4K5 p.Pro7Leu (c.20C>T)?

AlphaMissense predicts likely benign (score 0.154) — an in-silico prediction, not a clinical call.

MAP4K5 p.Pro7Leu

c.20C>T · VCV3870337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.154 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.154	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 56 kb · p 0.63 · regional, not allelic
Overall
CADD	24.7	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 0.0142% Admixed American · 8/56,228 alleles

Filtering AF 0.007% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0051%

Overall 0.000508% 8/1,575,492 alleles · ultra-rare exomes 8/1,423,140 · genomes 0/152,352 · joint denominator

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.Pro7Leu
Coding: c.20C>T
MANE Select: NM_006575
Type: single nucleotide variant
Location: chr14:50532030 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.15

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-pro7leu (accessed [today's date]).

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