Is SPEF2 p.Ala58Ser (c.172G>T) pathogenic?

SPEF2 p.Ala58Ser (c.172G>T) is classified Likely benign in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1034); Rare (popmax 0.388%, sas).

How common is SPEF2 p.Ala58Ser (c.172G>T) in the general population?

SPEF2 p.Ala58Ser (c.172G>T) is rare (popmax 0.388%, sas) (gnomAD).

What do computational predictors say about SPEF2 p.Ala58Ser (c.172G>T)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

SPEF2 p.Ala58Ser

c.172G>T · VCV4821833

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.388%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 0.88, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	18.99	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 0.388% South Asian · 352/90,724 alleles

Filtering AF 0.355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.341%

Overall 0.023% 371/1,612,588 alleles · rare exomes 345/1,460,396 · genomes 26/152,192 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.388%	258
Remaining individualsnot grpmax-eligible	0.0256%	3,903
Middle Eastern	0.0165%	6,046
European (non-Finnish)	0.00017%	589,671

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.Ala58Ser
Coding: c.172G>T
MANE Select: NM_024867
Type: single nucleotide variant
Location: chr5:35641441 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 58: the calponin-homology (ch) domain

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

Similar variants

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
SPEF2 c.2141+130C>T 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-ala58ser (accessed [today's date]).

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