Is MAP4K2 p.Gly675Ser (c.2023G>A) pathogenic?

MAP4K2 p.Gly675Ser (c.2023G>A) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.1051); Ultra-rare (popmax 0.0491%, amr).

How common is MAP4K2 p.Gly675Ser (c.2023G>A) in the general population?

MAP4K2 p.Gly675Ser (c.2023G>A) is ultra-rare (popmax 0.0491%, amr) (gnomAD).

What do computational predictors say about MAP4K2 p.Gly675Ser (c.2023G>A)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

MAP4K2 p.Gly675Ser

c.2023G>A · rs753057121 · VCV2348220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0491%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -8.55	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	22.7	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 0.0491% Admixed American · 29/59,014 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.00785% 126/1,604,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0491%	2,035
South Asian	0.0224%	4,471
Middle Eastern	0.0165%	6,066
East Asian	0.0157%	6,369
Remaining individualsnot grpmax-eligible	0.00645%	15,501
African / African-American	0.00535%	18,694
European (non-Finnish)	0.0051%	19,602
Finnishnot grpmax-eligible	0.00162%	61,894

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: MAP4K2
Protein: p.Gly675Ser
Coding: c.2023G>A
MANE Select: NM_004579
dbSNP: rs753057121
Type: single nucleotide variant
Location: chr11:64791978 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 675: the cnh domain

Full MAP4K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K2 p.Ala120Ser Benign ★★ same type
MAP4K2 p.Asn606= Benign ★★ same type
MAP4K2 p.Ala183Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala184Ser Uncertain significance ★ same type
MAP4K2 p.Ala405Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala487Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala790Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala806Val 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/map4k2-p-gly675ser (accessed [today's date]).

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