Is SPEF2 p.Ala384Asp (c.1151C>A) pathogenic?

SPEF2 p.Ala384Asp (c.1151C>A) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: likely pathogenic (0.8047); Very rare (popmax 0.00536%, afr); Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Ala384Asp (c.1151C>A)?

SPEF2 p.Ala384Asp (c.1151C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Ala384Asp (c.1151C>A) in the general population?

SPEF2 p.Ala384Asp (c.1151C>A) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about SPEF2 p.Ala384Asp (c.1151C>A)?

AlphaMissense predicts likely pathogenic (score 0.8047) — an in-silico prediction, not a clinical call.

SPEF2 p.Ala384Asp

c.1151C>A · VCV3322109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8047	likely pathogenic · top 8% in SPEF2
REVEL	0.5	indeterminate
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	27.1	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 0.00536% African / African-American · 4/74,694 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000622% 10/1,608,712 alleles · very rare exomes 8/1,456,578 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,674
European (non-Finnish)	0.00051%	196,159

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: SPEF2
Protein: p.Ala384Asp
Coding: c.1151C>A
MANE Select: NM_024867
Type: single nucleotide variant
Location: chr5:35659191 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 384: a UniProt-annotated variant site (in spgf43; loss of protein expression; changed sperm axoneme assembly)

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-ala384asp (accessed [today's date]).

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