Is SPRED1 p.Asp397= (c.1191C>T) pathogenic?

SPRED1 p.Asp397= (c.1191C>T) is classified Likely benign in SPRED1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). Ultra-rare (popmax 0.0167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with SPRED1 p.Asp397= (c.1191C>T)?

SPRED1 p.Asp397= (c.1191C>T) is associated with Cardiovascular phenotype, Legius syndrome (ClinVar).

How common is SPRED1 p.Asp397= (c.1191C>T) in the general population?

SPRED1 p.Asp397= (c.1191C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

SPRED1 p.Asp397=

c.1191C>T · rs749745659 · VCV536694

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.067	GERP -4.2, phastCons 0.97
Overall
CADD	8.611	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,986 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00192% 31/1,613,938 alleles · ultra-rare exomes 29/1,461,854 · genomes 2/152,084 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00267%	37,440
South Asian	0.0022%	45,534
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.00127%	78,666

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: SPRED1
Protein: p.Asp397=
Coding: c.1191C>T
MANE Select: NM_152594
dbSNP: rs749745659
Type: single nucleotide variant
Location: chr15:38351520 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.67 · 3 PDB
Residue 397: the spr domain; the 'required for interaction with tesk1' region

Full SPRED1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Legius syndrome

Similar variants

SPRED1 p.Asp397Asn Uncertain significance ★★ same residue
SPRED1 p.Asp397Gly Uncertain significance ★ ⚠ same residue
SPRED1 p.Arg117Ter Pathogenic ★★ same condition
SPRED1 p.Arg16Ter Pathogenic ★★ same condition
SPRED1 p.Arg18Ter Pathogenic ★★ same condition
SPRED1 p.Arg24Ter Pathogenic ★★ same condition
SPRED1 p.Arg251Ter Pathogenic/Likely pathogenic ★★ same condition
SPRED1 p.Arg325Ter Pathogenic/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/spred1-p-asp397 (accessed [today's date]).

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