Is TUSC3 p.Pro7Ser (c.19C>T) pathogenic?

TUSC3 p.Pro7Ser (c.19C>T) is classified Uncertain significance in TUSC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-19). AlphaMissense: likely benign (0.0702); Ultra-rare (popmax 0.0629%, amr); Associated with intellectual disability, autosomal recessive 7.

What condition is associated with TUSC3 p.Pro7Ser (c.19C>T)?

TUSC3 p.Pro7Ser (c.19C>T) is associated with intellectual disability, autosomal recessive 7 (ClinVar).

How common is TUSC3 p.Pro7Ser (c.19C>T) in the general population?

TUSC3 p.Pro7Ser (c.19C>T) is ultra-rare (popmax 0.0629%, amr) (gnomAD).

What do computational predictors say about TUSC3 p.Pro7Ser (c.19C>T)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

TUSC3 p.Pro7Ser

c.19C>T · rs201741917 · VCV1325580

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0629%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal recessive 7

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.89	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 3.2	GERP 1.7, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 217 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.7	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 0.0629% Admixed American · 37/58,804 alleles

Filtering AF 0.0469% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0413%

Overall 0.00312% 50/1,601,690 alleles · ultra-rare exomes 24/1,449,412 · genomes 26/152,278 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0629%	1,589
Remaining individualsnot grpmax-eligible	0.0177%	5,634
African / African-American	0.0027%	37,019

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: TUSC3
Protein: p.Pro7Ser
Coding: c.19C>T
MANE Select: NM_006765
dbSNP: rs201741917
Type: single nucleotide variant
Location: chr8:15540449 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.78 · 4 PDB

Full TUSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal recessive 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TUSC3 p.Arg74Ter Likely pathogenic ★★ same condition
TUSC3 p.Gln177Ter Pathogenic ★★ same condition
TUSC3 p.Ser331Ter Pathogenic/Likely pathogenic ★★ same condition
TUSC3 p.Ala13Val Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg15Gln Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg15Pro Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg9Gly Uncertain significance ★★ ⚠ same condition
TUSC3 c.1028+11T>C Benign/Likely benign ★★ 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/tusc3-p-pro7ser (accessed [today's date]).

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