Is MAP4K4 p.Arg740Ser (c.2220G>C) pathogenic?

MAP4K4 p.Arg740Ser (c.2220G>C) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: likely pathogenic (0.9511); Very rare (popmax 0.0011%, sas).

How common is MAP4K4 p.Arg740Ser (c.2220G>C) in the general population?

MAP4K4 p.Arg740Ser (c.2220G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MAP4K4 p.Arg740Ser (c.2220G>C)?

AlphaMissense predicts likely pathogenic (score 0.9511) — an in-silico prediction, not a clinical call.

MAP4K4 p.Arg740Ser

c.2220G>C · VCV4055780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9511	likely pathogenic
REVEL	0.257	benign-leaning
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP -2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1e-07 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R662S vs ClinVar R740S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,056 alleles

Overall 6.2e-05% 1/1,612,914 alleles · very rare exomes 1/1,460,760 · genomes 0/152,154 · 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: MAP4K4
Protein: p.Arg740Ser
Coding: c.2220G>C
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101866443 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 662 UniProt numbering: the 'disordered' region

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-arg740ser (accessed [today's date]).

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