Is MAP4K5 p.Arg552Gln (c.1655G>A) pathogenic?

MAP4K5 p.Arg552Gln (c.1655G>A) is classified Uncertain significance in MAP4K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.3174); Ultra-rare (popmax 0.0341%, mid).

How common is MAP4K5 p.Arg552Gln (c.1655G>A) in the general population?

MAP4K5 p.Arg552Gln (c.1655G>A) is ultra-rare (popmax 0.0341%, mid) (gnomAD).

What do computational predictors say about MAP4K5 p.Arg552Gln (c.1655G>A)?

AlphaMissense predicts likely benign (score 0.3174) — an in-silico prediction, not a clinical call.

MAP4K5 p.Arg552Gln

c.1655G>A · rs55997280 · VCV2563907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3174 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3174	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -10.83	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.43 · evaluated, not missing
Pangolin	Δ0.25	loss · gain 0.03 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 0.0017 · regional, not allelic
Overall
CADD	27.8	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

Grpmax group 0.0341% Middle Eastern · 2/5,870 alleles

Filtering AF 0.0301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.0253% 382/1,511,570 alleles · ultra-rare exomes 363/1,359,614 · genomes 19/151,956 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0341%	2,935
European (non-Finnish)	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.017%	5,875
African / African-American	0.007%	14,281
Admixed American	0.00192%	52,052

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.Arg552Gln
Coding: c.1655G>A
MANE Select: NM_006575
dbSNP: rs55997280
Type: single nucleotide variant
Location: chr14:50440063 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.15
Residue 552: a UniProt-annotated variant site (in); the cnh domain

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-arg552gln (accessed [today's date]).

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