Is SPRED1 p.Val348= (c.1044T>C) pathogenic?

SPRED1 p.Val348= (c.1044T>C) is classified Benign in SPRED1 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-04). Common (popmax 89.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with SPRED1 p.Val348= (c.1044T>C)?

SPRED1 p.Val348= (c.1044T>C) is associated with Cardiovascular phenotype, Legius syndrome (ClinVar).

SPRED1 p.Val348=

Q: How common is SPRED1 p.Val348= (c.1044T>C) in the general population?

SPRED1 p.Val348= (c.1044T>C) is common (popmax 89.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1044T>C · rs3751526 · VCV41370

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

gnomAD v4.1

Common

common (popmax 89.9%, nfe) — too common for a highly-penetrant pathogenic allele

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 2.8	GERP 1.3, phastCons 1
Overall
CADD	8.709	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 89.9% European (non-Finnish) · 1,060,633/1,180,002 alleles

Filtering AF 89.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 89.7%

Overall 88.2% 1,422,966/1,613,954 alleles · common exomes 1,297,707/1,461,840 · genomes 125,259/152,114 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	93.3%	1
Ashkenazi Jewishnot grpmax-eligible	90.6%	1
European (non-Finnish)grpmax	89.9%	1
South Asian	89.1%	1
Remaining individualsnot grpmax-eligible	87.3%	1
Middle Eastern	84%	1
Admixed American	83.5%	1
East Asian	78.5%	1
Amishnot grpmax-eligible	74.7%	1
African / African-American	65.4%	2

Finnish 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: SPRED1
Protein: p.Val348=
Coding: c.1044T>C
MANE Select: NM_152594
dbSNP: rs3751526
Type: single nucleotide variant
Location: chr15:38351373 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.67 · 3 PDB
Residue 348: 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.Val348Gly Likely benign ★ same residue
SPRED1 p.Val348_Arg349= 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-val348 (accessed [today's date]).

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