Is SPAG5 p.Ser14Pro (c.40T>C) pathogenic?

SPAG5 p.Ser14Pro (c.40T>C) is classified Uncertain significance in SPAG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1122); Absent from gnomAD v4.1.

How common is SPAG5 p.Ser14Pro (c.40T>C) in the general population?

SPAG5 p.Ser14Pro (c.40T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPAG5 p.Ser14Pro (c.40T>C)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

SPAG5 p.Ser14Pro

c.40T>C · VCV4172538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -7.78	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 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 6,587 bp · p 0.18 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPAG5
Protein: p.Ser14Pro
Coding: c.40T>C
MANE Select: NM_006461
Type: single nucleotide variant
Location: chr17:28598907 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.81
Residue 14: the 'disordered' region; a modified residue (phosphoserine)

Full SPAG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPAG5 p.Met1129Lys Uncertain significance ★★ ⚠ same type
SPAG5 p.Gly123Asp Likely benign ★★ same type
SPAG5 c.3354+1G>A Uncertain significance ★ same type
SPAG5 p.Ala1025Thr Uncertain significance ★ ⚠ same type
SPAG5 p.Ala175Val Uncertain significance ★ ⚠ same type
SPAG5 p.Ala187Val Uncertain significance ★ ⚠ same type
SPAG5 p.Ala239Thr Uncertain significance ★ ⚠ same type
SPAG5 p.Ala255Thr Uncertain significance ★ ⚠ 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/spag5-p-ser14pro (accessed [today's date]).

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