Is SPEF2 p.Ser53Cys (c.157A>T) pathogenic?

SPEF2 p.Ser53Cys (c.157A>T) is classified Uncertain significance in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.1551); Ultra-rare (popmax 0.0187%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPEF2 p.Ser53Cys (c.157A>T)?

SPEF2 p.Ser53Cys (c.157A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEF2 p.Ser53Cys (c.157A>T) in the general population?

SPEF2 p.Ser53Cys (c.157A>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about SPEF2 p.Ser53Cys (c.157A>T)?

AlphaMissense predicts likely benign (score 0.1551) — an in-silico prediction, not a clinical call.

SPEF2 p.Ser53Cys

c.157A>T · VCV3960846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1551 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1551	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 197 kb · p 0.46 · regional, not allelic
Overall
CADD	24.2	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 0.0187% South Asian · 17/90,746 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00979%

Overall 0.00168% 27/1,602,978 alleles · ultra-rare exomes 26/1,450,780 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,338
Remaining individualsnot grpmax-eligible	0.0113%	8,867
East Asian	0.00223%	44,834
Admixed American	0.00167%	59,916
European (non-Finnish)	8.54e-05%	1,170,285

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.Ser53Cys
Coding: c.157A>T
MANE Select: NM_024867
Type: single nucleotide variant
Location: chr5:35628558 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.30
Residue 53: the calponin-homology (ch) domain

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.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
SPEF2 p.Ala1772Thr 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-ser53cys (accessed [today's date]).

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