Is SPEF2 p.Phe136Leu (c.406T>C) pathogenic?

SPEF2 p.Phe136Leu (c.406T>C) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.908); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Phe136Leu (c.406T>C)?

SPEF2 p.Phe136Leu (c.406T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Phe136Leu (c.406T>C) in the general population?

SPEF2 p.Phe136Leu (c.406T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPEF2 p.Phe136Leu (c.406T>C)?

AlphaMissense predicts likely pathogenic (score 0.908) — an in-silico prediction, not a clinical call.

SPEF2 p.Phe136Leu

c.406T>C · VCV4631935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.908 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.908	likely pathogenic · top 4% in SPEF2
REVEL	0.191	benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	21.5	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

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: SPEF2
Protein: p.Phe136Leu
Coding: c.406T>C
MANE Select: NM_024867
Type: single nucleotide variant
Location: chr5:35641675 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30

Full SPEF2 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

SPEF2 p.Asp797Gly Uncertain significance ★★ ⚠ same condition
SPEF2 p.Glu116Lys Uncertain significance ★★ ⚠ same condition
SPEF2 p.Glu1752Gln Uncertain significance ★★ ⚠ same condition
SPEF2 p.Ala1122Thr Uncertain significance ★ ⚠ same condition
SPEF2 p.Ala1323Val Uncertain significance ★ ⚠ same condition
SPEF2 p.Ala1355Thr Uncertain significance ★ ⚠ same condition
SPEF2 p.Ala1405Ser Uncertain significance ★ ⚠ same condition
SPEF2 p.Ala1772Thr 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/spef2-p-phe136leu (accessed [today's date]).

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