Is SNCAIP p.Ser552Ala (c.1654T>G) pathogenic?

SNCAIP p.Ser552Ala (c.1654T>G) is classified Uncertain significance in SNCAIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.0674); Very rare (popmax 0.00833%, amr).

How common is SNCAIP p.Ser552Ala (c.1654T>G) in the general population?

SNCAIP p.Ser552Ala (c.1654T>G) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about SNCAIP p.Ser552Ala (c.1654T>G)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

SNCAIP p.Ser552Ala

c.1654T>G · VCV3959186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.25	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 3.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 72 kb · p 0.00024 · regional, not allelic
Overall
CADD	16.76	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

Grpmax group 0.00833% Admixed American · 5/60,018 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000806% 13/1,613,740 alleles · very rare exomes 13/1,461,460 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000593%	168,528

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: SNCAIP
Protein: p.Ser552Ala
Coding: c.1654T>G
MANE Select: NM_005460
Type: single nucleotide variant
Location: chr5:122449906 (GRCh38)
Gene constraint: LOEUF 0.636 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.98 · 1 PDB
Residue 552: the 'disordered' region; an α-helix

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

Similar variants

SNCAIP p.Ala358Val Uncertain significance ★★ ⚠ same type
SNCAIP p.Ala363Thr Uncertain significance ★★ ⚠ same type
SNCAIP p.Glu237Lys Uncertain significance ★★ ⚠ same type
SNCAIP p.Leu148= Uncertain significance ★★ same type
SNCAIP p.Ser912Arg Uncertain significance ★★ ⚠ same type
SNCAIP p.Val461Ile Uncertain significance ★★ ⚠ same type
SNCAIP c.*103C>T Likely benign ★★ same type
SNCAIP c.*46T>G Likely 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/sncaip-p-ser552ala (accessed [today's date]).

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