Is SPRED1 p.Phe412Ser (c.1235T>C) pathogenic?

SPRED1 p.Phe412Ser (c.1235T>C) is classified Uncertain significance in SPRED1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-24). AlphaMissense: likely pathogenic (0.6392); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with SPRED1 p.Phe412Ser (c.1235T>C)?

SPRED1 p.Phe412Ser (c.1235T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is SPRED1 p.Phe412Ser (c.1235T>C) in the general population?

SPRED1 p.Phe412Ser (c.1235T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPRED1 p.Phe412Ser (c.1235T>C)?

AlphaMissense predicts likely pathogenic (score 0.6392) — an in-silico prediction, not a clinical call.

SPRED1 p.Phe412Ser

c.1235T>C · VCV4827631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6392 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6392	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -13.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 579 bp · p 0.01 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPRED1
Protein: p.Phe412Ser
Coding: c.1235T>C
MANE Select: NM_152594
Type: single nucleotide variant
Location: chr15:38351564 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.67 · 3 PDB
Residue 412: 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

Similar variants

SPRED1 p.Phe412Leu Uncertain significance ★ ⚠ same residue
SPRED1 p.Arg16Ter Pathogenic ★★ same condition
SPRED1 p.Ala137Val Uncertain significance ★★ ⚠ same condition
SPRED1 p.Ala183Thr Uncertain significance ★★ ⚠ same condition
SPRED1 p.Ala19Gly Uncertain significance ★★ ⚠ same condition
SPRED1 p.Ala406Val Uncertain significance ★★ ⚠ same condition
SPRED1 p.Arg118Lys Uncertain significance ★★ ⚠ same condition
SPRED1 p.Arg16Gln 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/spred1-p-phe412ser (accessed [today's date]).

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