Is SPPL2A p.Phe353Ser (c.1058T>C) pathogenic?

SPPL2A p.Phe353Ser (c.1058T>C) is classified Uncertain significance in SPPL2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-27). AlphaMissense: likely pathogenic (0.9566); Very rare (popmax 0.00169%, amr).

How common is SPPL2A p.Phe353Ser (c.1058T>C) in the general population?

SPPL2A p.Phe353Ser (c.1058T>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about SPPL2A p.Phe353Ser (c.1058T>C)?

AlphaMissense predicts likely pathogenic (score 0.9566) — an in-silico prediction, not a clinical call.

SPPL2A p.Phe353Ser

c.1058T>C · rs1322444174 · VCV1972997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9566	likely pathogenic
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.0052 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00169% Admixed American · 1/59,336 alleles

Overall 6.6e-05% 1/1,514,584 alleles · very rare exomes 1/1,362,246 · genomes 0/152,338 · joint denominator

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: SPPL2A
Protein: p.Phe353Ser
Coding: c.1058T>C
MANE Select: NM_032802
dbSNP: rs1322444174
Type: single nucleotide variant
Location: chr15:50730996 (GRCh38)
Gene constraint: LOEUF 1.074 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 2 PDB

Full SPPL2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPPL2A p.Ala179Val Uncertain significance ★★ ⚠ same type
SPPL2A p.Ala298Val Uncertain significance ★★ ⚠ same type
SPPL2A p.Ala480Thr Uncertain significance ★★ ⚠ same type
SPPL2A p.Arg281Cys Uncertain significance ★★ ⚠ same type
SPPL2A p.Arg281His Uncertain significance ★★ ⚠ same type
SPPL2A p.Arg424Thr Uncertain significance ★★ ⚠ same type
SPPL2A p.Arg483His Uncertain significance ★★ same type
SPPL2A p.Asn66Thr 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/sppl2a-p-phe353ser (accessed [today's date]).

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