Is SPEF2 p.Ala934Pro (c.2800G>C) pathogenic?

SPEF2 p.Ala934Pro (c.2800G>C) is classified Benign in SPEF2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-07-15). AlphaMissense: likely benign (0.0582); Common (popmax 82.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with spermatogenic failure 43.

What condition is associated with SPEF2 p.Ala934Pro (c.2800G>C)?

SPEF2 p.Ala934Pro (c.2800G>C) is associated with spermatogenic failure 43 (ClinVar).

What do computational predictors say about SPEF2 p.Ala934Pro (c.2800G>C)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

SPEF2 p.Ala934Pro

Q: How common is SPEF2 p.Ala934Pro (c.2800G>C) in the general population?

SPEF2 p.Ala934Pro (c.2800G>C) is common (popmax 82.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2800G>C · rs13170390 · VCV403479

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 82.4%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 43

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.24	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 -5.4	GERP -3.1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	0.03	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 82.4% Middle Eastern · 4,992/6,058 alleles

Filtering AF 80.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.7%

Overall 77.6% 1,251,449/1,613,346 alleles · common exomes 1,137,128/1,461,264 · genomes 114,321/152,082 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	82.8%	1
Middle Easterngrpmax	82.4%	1
Ashkenazi Jewishnot grpmax-eligible	80%	1
East Asian	79.7%	1
European (non-Finnish)	79.1%	1
Remaining individualsnot grpmax-eligible	77.5%	1
Finnishnot grpmax-eligible	77.1%	1
Admixed American	71.2%	1
South Asian	69.9%	1
African / African-American	66.4%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala934Pro
Coding: c.2800G>C
MANE Select: NM_024867
dbSNP: rs13170390
Type: single nucleotide variant
Location: chr5:35709082 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 934: the 'disordered' region; 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 (in)

Full SPEF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 43 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPEF2 c.1167+46T>C Benign ★★ same condition
SPEF2 c.2914+19T>G Benign ★★ same condition
SPEF2 c.3331-11T>C Benign ★★ same condition
SPEF2 p.Ala904Val Benign ★★ same condition
SPEF2 p.Asn714= Benign ★★ same condition
SPEF2 p.Asn71His Benign ★★ same condition
SPEF2 p.Asp287= Benign ★★ same condition
SPEF2 p.Ile193= Benign ★★ 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-ala934pro (accessed [today's date]).

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