Is SPEF2 p.Pro545Ser (c.1633C>T) pathogenic?

SPEF2 p.Pro545Ser (c.1633C>T) is classified Likely benign in SPEF2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1211); Rare (popmax 0.264%, nfe); Associated with spermatogenic failure 43.

What condition is associated with SPEF2 p.Pro545Ser (c.1633C>T)?

SPEF2 p.Pro545Ser (c.1633C>T) is associated with spermatogenic failure 43 (ClinVar).

How common is SPEF2 p.Pro545Ser (c.1633C>T) in the general population?

SPEF2 p.Pro545Ser (c.1633C>T) is rare (popmax 0.264%, nfe) (gnomAD).

What do computational predictors say about SPEF2 p.Pro545Ser (c.1633C>T)?

AlphaMissense predicts likely benign (score 0.1211) — an in-silico prediction, not a clinical call.

SPEF2 p.Pro545Ser

c.1633C>T · rs185000070 · VCV769650

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1211 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 43

Computational evidence

Protein change
AlphaMissense	0.1211	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.92	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 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	22.1	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 0.264% European (non-Finnish) · 3,112/1,179,964 alleles

Filtering AF 0.256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.253%

Overall 0.227% 3,658/1,614,052 alleles · rare exomes 3,430/1,461,786 · genomes 228/152,266 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.264%	379
Middle Eastern	0.248%	404
South Asian	0.235%	426
Remaining individualsnot grpmax-eligible	0.213%	470
Ashkenazi Jewishnot grpmax-eligible	0.182%	548
Admixed American	0.137%	732
African / African-American	0.0373%	2,679
Finnishnot grpmax-eligible	0.0297%	3,369
East Asian	0.00223%	44,866

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.Pro545Ser
Coding: c.1633C>T
MANE Select: NM_024867
dbSNP: rs185000070
Type: single nucleotide variant
Location: chr5:35691145 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 545: 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

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.Ala934Pro Benign ★★ same condition
SPEF2 p.Asn714= Benign ★★ same condition
SPEF2 p.Asn71His Benign ★★ same condition
SPEF2 p.Asp287= 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-pro545ser (accessed [today's date]).

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