Is MAP4K4 p.Ser953Phe (c.2858C>T) pathogenic?

MAP4K4 p.Ser953Phe (c.2858C>T) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). Very rare (popmax 0.00196%, amr); Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Ser953Phe (c.2858C>T)?

MAP4K4 p.Ser953Phe (c.2858C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Ser953Phe (c.2858C>T) in the general population?

MAP4K4 p.Ser953Phe (c.2858C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

MAP4K4 p.Ser953Phe

c.2858C>T · rs555033539 · VCV2401432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.313	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1e-07 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,988 alleles

Overall 0.00013% 2/1,536,454 alleles · very rare exomes 1/1,384,184 · genomes 1/152,270 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	50,988
European (non-Finnish)	8.72e-05%	1,146,946

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.Ser953Phe
Coding: c.2858C>T
MANE Select: NM_001395002
dbSNP: rs555033539
Type: single nucleotide variant
Location: chr2:101871591 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 953: the cnh domain; the 'mediates interaction with rap2a' region

Full MAP4K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP4K4 p.Arg1329Ter Pathogenic/Likely pathogenic ★★ same condition
MAP4K4 p.Ala491Pro Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Leu742Pro Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Asp203Gly Likely pathogenic ★ same condition
MAP4K4 p.Gln402Ter Pathogenic ★ same condition
MAP4K4 p.Gly173Asp Pathogenic ★ same condition
MAP4K4 p.Lys54Arg Likely pathogenic ★ same condition

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-ser953phe (accessed [today's date]).

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