Is SPTB p.Arg2001His (c.6002G>A) pathogenic?

SPTB p.Arg2001His (c.6002G>A) is classified Uncertain significance in SPTB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.184); Ultra-rare (popmax 0.0494%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPTB p.Arg2001His (c.6002G>A)?

SPTB p.Arg2001His (c.6002G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPTB p.Arg2001His (c.6002G>A) in the general population?

SPTB p.Arg2001His (c.6002G>A) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about SPTB p.Arg2001His (c.6002G>A)?

AlphaMissense predicts likely benign (score 0.184) — an in-silico prediction, not a clinical call.

SPTB p.Arg2001His

c.6002G>A · rs148593138 · VCV2381044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.184	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 46 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.0	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 0.0494% South Asian · 45/91,092 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00762% 123/1,613,338 alleles · ultra-rare exomes 104/1,461,126 · genomes 19/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
African / African-American	0.036%	2,775
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Middle Eastern	0.0164%	6,082
East Asian	0.00668%	14,961
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.005%	20,003
European (non-Finnish)	0.0028%	35,757

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: SPTB
Protein: p.Arg2001His
Coding: c.6002G>A
MANE Select: NM_001355436
dbSNP: rs148593138
Type: single nucleotide variant
Location: chr14:64769054 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 6 PDB
Residue 2001: an α-helix

Full SPTB 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

SPTB p.Arg2001Cys Uncertain significance ★ ⚠ same residue
SPTB p.Ala1152Gly Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1180Thr Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1632Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1741Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1760Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1795Thr Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1903Val Uncertain significance ★★ ⚠ 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/sptb-p-arg2001his (accessed [today's date]).

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