Is SPTLC3 p.Pro44Ala (c.130C>G) pathogenic?

SPTLC3 p.Pro44Ala (c.130C>G) is classified Uncertain significance in SPTLC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.0697); Ultra-rare (popmax 0.0403%, amr).

How common is SPTLC3 p.Pro44Ala (c.130C>G) in the general population?

SPTLC3 p.Pro44Ala (c.130C>G) is ultra-rare (popmax 0.0403%, amr) (gnomAD).

What do computational predictors say about SPTLC3 p.Pro44Ala (c.130C>G)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

SPTLC3 p.Pro44Ala

c.130C>G · rs374808387 · VCV3169748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0403%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0697	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -6.08	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 -1.3	GERP -3.8
Regional constraint	o/e 0.91	unconstrained · MANE · 156 kb · p 0.022 · regional, not allelic
Overall
CADD	0.659	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 0.0403% Admixed American · 19/47,200 alleles

Filtering AF 0.0263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00399% 62/1,553,624 alleles · ultra-rare exomes 36/1,401,430 · genomes 26/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0403%	2,484
African / African-American	0.0264%	3,791
Remaining individualsnot grpmax-eligible	0.0184%	5,438
European (non-Finnish)	0.00113%	88,851

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: SPTLC3
Protein: p.Pro44Ala
Coding: c.130C>G
MANE Select: NM_018327
dbSNP: rs374808387
Type: single nucleotide variant
Location: chr20:13048957 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.25

Full SPTLC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPTLC3 p.Trp150Arg Likely pathogenic ★ ⚠ same type
SPTLC3 p.Ala133Val Uncertain significance ★ ⚠ same type
SPTLC3 p.Ala262Ser Uncertain significance ★ ⚠ same type
SPTLC3 p.Ala38Thr Uncertain significance ★ ⚠ same type
SPTLC3 p.Ala500Ser Uncertain significance ★ ⚠ same type
SPTLC3 p.Ala519Val Uncertain significance ★ ⚠ same type
SPTLC3 p.Ala93Thr Uncertain significance ★ ⚠ same type
SPTLC3 p.Arg128Gln 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/sptlc3-p-pro44ala (accessed [today's date]).

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