Is SPEF2 p.Val718Met (c.2152G>A) pathogenic?

SPEF2 p.Val718Met (c.2152G>A) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.0972); Very rare (popmax 0.00838%, amr); Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Val718Met (c.2152G>A)?

SPEF2 p.Val718Met (c.2152G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Val718Met (c.2152G>A) in the general population?

SPEF2 p.Val718Met (c.2152G>A) is very rare (popmax 0.00838%, amr) (gnomAD).

What do computational predictors say about SPEF2 p.Val718Met (c.2152G>A)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

SPEF2 p.Val718Met

c.2152G>A · rs923104734 · VCV3168834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00838%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -3.9
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	6.336	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 0.00838% Admixed American · 5/59,694 alleles

Filtering AF 0.00325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.000807% 13/1,611,106 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00838%	11,939
Remaining individualsnot grpmax-eligible	0.0016%	62,336
European (non-Finnish)	0.000594%	168,405

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.Val718Met
Coding: c.2152G>A
MANE Select: NM_024867
dbSNP: rs923104734
Type: single nucleotide variant
Location: chr5:35700506 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 718: 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)

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-val718met (accessed [today's date]).

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