Is SPPL2A p.Pro79Ser (c.235C>T) pathogenic?

SPPL2A p.Pro79Ser (c.235C>T) is classified Uncertain significance in SPPL2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). AlphaMissense: likely benign (0.1118); Very rare (popmax 0.00221%, sas).

How common is SPPL2A p.Pro79Ser (c.235C>T) in the general population?

SPPL2A p.Pro79Ser (c.235C>T) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about SPPL2A p.Pro79Ser (c.235C>T)?

AlphaMissense predicts likely benign (score 0.1118) — an in-silico prediction, not a clinical call.

SPPL2A p.Pro79Ser

c.235C>T · rs775631091 · VCV2751782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1118	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -12.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.0052 · regional, not allelic
Overall
CADD	21.7	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 0.00221% South Asian · 2/90,584 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,611,158 alleles · very rare exomes 2/1,458,888 · genomes 0/152,270 · 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.Pro79Ser
Coding: c.235C>T
MANE Select: NM_032802
dbSNP: rs775631091
Type: single nucleotide variant
Location: chr15:50748813 (GRCh38)
Gene constraint: LOEUF 1.074 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 2 PDB
Residue 79: the pa domain

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

Similar variants

SPPL2A p.Pro79Ala Uncertain significance ★★ ⚠ same residue
SPPL2A p.Pro79Arg Uncertain significance ★ ⚠ same residue
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

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-pro79ser (accessed [today's date]).

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