Is MAPKBP1 p.Arg577His (c.1730G>A) pathogenic?

MAPKBP1 p.Arg577His (c.1730G>A) is classified Uncertain significance in MAPKBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely benign (0.2104); Very rare (popmax 0.00659%, sas).

How common is MAPKBP1 p.Arg577His (c.1730G>A) in the general population?

MAPKBP1 p.Arg577His (c.1730G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about MAPKBP1 p.Arg577His (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

MAPKBP1 p.Arg577His

c.1730G>A · VCV4924337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 5,625 bp · p 4.8e-14 · regional, not allelic
Overall
CADD	32.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R583H vs ClinVar R577H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,092 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00248% 40/1,613,908 alleles · very rare exomes 38/1,461,774 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,182
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00254%	39,332

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: MAPKBP1
Protein: p.Arg577His
Coding: c.1730G>A
MANE Select: NM_014994
Type: single nucleotide variant
Location: chr15:41817406 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.84 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.82

Full MAPKBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPKBP1 p.Arg577Cys Uncertain significance ★★ ⚠ same residue
MAPKBP1 c.1711+5G>A Uncertain significance ★★ same type
MAPKBP1 p.Ala1126Pro Uncertain significance ★★ ⚠ same type
MAPKBP1 p.Ala1407Thr Uncertain significance ★★ ⚠ same type
MAPKBP1 p.Ala1427Ser Uncertain significance ★★ ⚠ same type
MAPKBP1 p.Ala146Thr Uncertain significance ★★ ⚠ same type
MAPKBP1 p.Arg1102Cys Uncertain significance ★★ ⚠ same type
MAPKBP1 p.Arg1314Trp 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/mapkbp1-p-arg577his (accessed [today's date]).

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