Is SPEF2 p.Val1386Phe (c.4156G>T) pathogenic?

SPEF2 p.Val1386Phe (c.4156G>T) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely benign (0.1666); Ultra-rare (popmax 0.0353%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Val1386Phe (c.4156G>T)?

SPEF2 p.Val1386Phe (c.4156G>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Val1386Phe (c.4156G>T) in the general population?

SPEF2 p.Val1386Phe (c.4156G>T) is ultra-rare (popmax 0.0353%, nfe) (gnomAD).

What do computational predictors say about SPEF2 p.Val1386Phe (c.4156G>T)?

AlphaMissense predicts likely benign (score 0.1666) — an in-silico prediction, not a clinical call.

SPEF2 p.Val1386Phe

c.4156G>T · rs199611608 · VCV2250335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0353%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1666	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2	GERP -4, phastCons 0.93
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	18.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0353% European (non-Finnish) · 416/1,179,510 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.0266% 429/1,612,972 alleles · ultra-rare exomes 413/1,460,794 · genomes 16/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0353%	2,835
Remaining individualsnot grpmax-eligible	0.0128%	7,804
African / African-American	0.00534%	18,716
Finnishnot grpmax-eligible	0.00156%	63,998

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.Val1386Phe
Coding: c.4156G>T
MANE Select: NM_024867
dbSNP: rs199611608
Type: single nucleotide variant
Location: chr5:35776334 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 1386: a UniProt-annotated variant site (in spgf43; loss of protein expression; changed sperm axoneme assembly); a UniProt-annotated variant site (found in a female patient with primary ciliary dyskinesia-like symptoms including chronic sinusitis, bronchitis, chronic wet cough and recurrent pneumonia; uncertain significance); a UniProt-annotated variant site (found in 2 brothers with severe asthenozoospermia and a primary ciliary dyskinesia-like phenotype with recurrent airway infections, bronchiectasis, rhinosinusitis and otitis media; likely pathogenic); the 'interaction with ift20' region

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-val1386phe (accessed [today's date]).

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