Is SPEF2 p.Ile193= (c.579T>C) pathogenic?

SPEF2 p.Ile193= (c.579T>C) is classified Benign in SPEF2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-07-15). Common (popmax 87.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with spermatogenic failure 43.

What condition is associated with SPEF2 p.Ile193= (c.579T>C)?

SPEF2 p.Ile193= (c.579T>C) is associated with spermatogenic failure 43 (ClinVar).

SPEF2 p.Ile193=

Q: How common is SPEF2 p.Ile193= (c.579T>C) in the general population?

SPEF2 p.Ile193= (c.579T>C) is common (popmax 87.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.579T>C · rs7706444 · VCV403472

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 87.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

spermatogenic failure 43

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.9	GERP -2.9
Overall
CADD	0.357	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 87.4% East Asian · 39,010/44,644 alleles

Filtering AF 86.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 86.4%

Overall 66.6% 1,059,588/1,591,038 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	87.4%	1
South Asian	81.1%	1
African / African-American	77.6%	1
Admixed American	76.5%	1
Remaining individualsnot grpmax-eligible	67.8%	1
Ashkenazi Jewishnot grpmax-eligible	65.9%	2
Middle Eastern	65.5%	2
European (non-Finnish)	63.8%	2
Finnishnot grpmax-eligible	62.9%	2
Amishnot grpmax-eligible	50.9%	2

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.Ile193=
Coding: c.579T>C
MANE Select: NM_024867
dbSNP: rs7706444
Type: single nucleotide variant
Location: chr5:35644519 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30

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-ile193 (accessed [today's date]).

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