Is SPEF2 p.Arg337Gln (c.1010G>A) pathogenic?

SPEF2 p.Arg337Gln (c.1010G>A) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: ambiguous (0.4344); Ultra-rare (popmax 0.0527%, afr); Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Arg337Gln (c.1010G>A)?

SPEF2 p.Arg337Gln (c.1010G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Arg337Gln (c.1010G>A) in the general population?

SPEF2 p.Arg337Gln (c.1010G>A) is ultra-rare (popmax 0.0527%, afr) (gnomAD).

What do computational predictors say about SPEF2 p.Arg337Gln (c.1010G>A)?

AlphaMissense predicts ambiguous (score 0.4344) — an in-silico prediction, not a clinical call.

SPEF2 p.Arg337Gln

c.1010G>A · rs139795958 · VCV2362396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4344 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4344	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -6.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	27.8	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 0.0527% African / African-American · 39/73,960 alleles

Filtering AF 0.0396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.00291% 46/1,581,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0527%	1,896
South Asian	0.0023%	43,521
Admixed American	0.00177%	56,516
Remaining individualsnot grpmax-eligible	0.00164%	61,032
European (non-Finnish)	0.000259%	386,766

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.Arg337Gln
Coding: c.1010G>A
MANE Select: NM_024867
dbSNP: rs139795958
Type: single nucleotide variant
Location: chr5:35659050 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 337: 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.Arg337Trp Uncertain significance ★ ⚠ same residue
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

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-arg337gln (accessed [today's date]).

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