Is SPTBN4 p.Ala1237Asp (c.3710C>A) pathogenic?

SPTBN4 p.Ala1237Asp (c.3710C>A) is classified Benign/Likely benign in SPTBN4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). AlphaMissense: ambiguous (0.3846); Rare (popmax 0.993%, nfe).

How common is SPTBN4 p.Ala1237Asp (c.3710C>A) in the general population?

SPTBN4 p.Ala1237Asp (c.3710C>A) is rare (popmax 0.993%, nfe) (gnomAD).

What do computational predictors say about SPTBN4 p.Ala1237Asp (c.3710C>A)?

AlphaMissense predicts ambiguous (score 0.3846) — an in-silico prediction, not a clinical call.

SPTBN4 p.Ala1237Asp

c.3710C>A · rs148009574 · VCV781881

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3846 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.993%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3846	ambiguous
REVEL	0.346	indeterminate
SaProt	LLR -11.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 61 kb · p 2.7e-11 · regional, not allelic
Overall
CADD	23.8	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 0.993% European (non-Finnish) · 11,713/1,179,846 alleles

Filtering AF 0.978% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.972%

Overall 0.793% 12,797/1,613,662 alleles · rare exomes 11,982/1,461,340 · genomes 815/152,322 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.98%	51
European (non-Finnish)grpmax	0.993%	101
Finnishnot grpmax-eligible	0.777%	129
Remaining individualsnot grpmax-eligible	0.605%	165
African / African-American	0.175%	573
Admixed American	0.0951%	1,052
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,788
South Asian	0.0011%	90,918

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SPTBN4
Protein: p.Ala1237Asp
Coding: c.3710C>A
MANE Select: NM_020971
dbSNP: rs148009574
Type: single nucleotide variant
Location: chr19:40523492 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.50
Residue 1237: a UniProt-annotated variant site (in nedhnd; decreased protein abundance in patient cells homozygous for the mutation)

Full SPTBN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPTBN4 p.Ala1237Gly Uncertain significance ★ ⚠ same residue
SPTBN4 c.2903+2T>C Likely pathogenic ★★ same type
SPTBN4 p.Ala1016Asp Uncertain significance ★★ ⚠ same type
SPTBN4 p.Ala1083Gly Uncertain significance ★★ ⚠ same type
SPTBN4 p.Ala1134Val Uncertain significance ★★ ⚠ same type
SPTBN4 p.Ala1393Val Uncertain significance ★★ ⚠ same type
SPTBN4 p.Ala1993Val Uncertain significance ★★ ⚠ same type
SPTBN4 p.Ala22Thr 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/sptbn4-p-ala1237asp (accessed [today's date]).

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