Is SNTA1 p.Pro74Ser (c.220C>T) pathogenic?

SNTA1 p.Pro74Ser (c.220C>T) is classified Uncertain significance in SNTA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). AlphaMissense: likely benign (0.0626); Very rare (popmax 0.00317%, eas); Associated with Cardiovascular phenotype.

What condition is associated with SNTA1 p.Pro74Ser (c.220C>T)?

SNTA1 p.Pro74Ser (c.220C>T) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is SNTA1 p.Pro74Ser (c.220C>T) in the general population?

SNTA1 p.Pro74Ser (c.220C>T) is very rare (popmax 0.00317%, eas) (gnomAD).

What do computational predictors say about SNTA1 p.Pro74Ser (c.220C>T)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

SNTA1 p.Pro74Ser

c.220C>T · rs1191500220 · VCV2078745

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00317%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.89	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, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 35 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	8.277	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 0.00317% East Asian · 1/31,574 alleles

Filtering AF 0.000138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000101%

Overall 0.000584% 7/1,198,348 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00317%	31,574
Remaining individualsnot grpmax-eligible	0.00197%	50,748
European (non-Finnish)	0.000472%	211,737

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: SNTA1
Protein: p.Pro74Ser
Coding: c.220C>T
MANE Select: NM_003098
dbSNP: rs1191500220
Type: single nucleotide variant
Location: chr20:33443401 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.00
Residue 74: the ph 1 domain; the 'disordered' region

Full SNTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome

Similar variants

SNTA1 p.Pro74Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SNTA1 p.Pro74Thr Uncertain significance ★ ⚠ same residue
SNTA1 p.Pro74= Likely benign ★ same residue
SNTA1 p.Pro74Ala Uncertain significance ★ ⚠ same residue
SNTA1 c.1425+1G>A Uncertain significance ★★ same condition
SNTA1 c.497-3C>T Uncertain significance ★★ same condition
SNTA1 c.497-5A>G Uncertain significance ★★ same condition
SNTA1 c.702-3C>T Uncertain significance ★★ same condition

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/snta1-p-pro74ser (accessed [today's date]).

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