Is SPEF2 p.Val648= (c.1944A>G) pathogenic?

SPEF2 p.Val648= (c.1944A>G) is classified Likely benign in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-01). Very rare (popmax 0.00424%, nfe).

How common is SPEF2 p.Val648= (c.1944A>G) in the general population?

SPEF2 p.Val648= (c.1944A>G) is very rare (popmax 0.00424%, nfe) (gnomAD).

SPEF2 p.Val648=

c.1944A>G · VCV4280937

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.7	GERP -3.6
Overall
CADD	0.762	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00424% European (non-Finnish) · 50/1,179,694 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00328% 53/1,613,410 alleles · very rare exomes 43/1,461,228 · genomes 10/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,594
Remaining individualsnot grpmax-eligible	0.0032%	31,219
Finnishnot grpmax-eligible	0.00156%	63,990

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.Val648=
Coding: c.1944A>G
MANE Select: NM_024867
Type: single nucleotide variant
Location: chr5:35694332 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 648: 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

Similar variants

SPEF2 p.Val648Leu Uncertain significance ★ ⚠ same residue
SPEF2 p.Asp797Gly Uncertain significance ★★ ⚠ same type
SPEF2 p.Glu116Lys Uncertain significance ★★ ⚠ same type
SPEF2 p.Glu1752Gln Uncertain significance ★★ ⚠ same type
SPEF2 c.1167+46T>C Benign ★★ same type
SPEF2 c.1168-85A>G Benign ★★ same type
SPEF2 c.1525-111C>G Benign ★★ same type
SPEF2 c.2037+17A>C Benign ★★ same type

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-val648 (accessed [today's date]).

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