Is STARD3 p.Leu289Pro (c.866T>C) pathogenic?

STARD3 p.Leu289Pro (c.866T>C) is classified Uncertain significance in STARD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.992); Very rare (popmax 0.00932%, nfe).

How common is STARD3 p.Leu289Pro (c.866T>C) in the general population?

STARD3 p.Leu289Pro (c.866T>C) is very rare (popmax 0.00932%, nfe) (gnomAD).

What do computational predictors say about STARD3 p.Leu289Pro (c.866T>C)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

STARD3 p.Leu289Pro

c.866T>C · rs766071568 · VCV2363045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic · top 8% in STARD3
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -14.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 9,373 bp · p 0.086 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00932% European (non-Finnish) · 110/1,180,026 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00706% 114/1,613,734 alleles · very rare exomes 112/1,461,540 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00932%	10,728
African / African-American	0.004%	24,976
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: STARD3
Protein: p.Leu289Pro
Coding: c.866T>C
MANE Select: NM_006804
dbSNP: rs766071568
Type: single nucleotide variant
Location: chr17:39660438 (GRCh38)
Gene constraint: LOEUF 0.812 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 5 PDB
Residue 289: the start domain; a β-strand

Full STARD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STARD3 p.Ala187Thr Uncertain significance ★ ⚠ same type
STARD3 p.Ala293Val Uncertain significance ★ ⚠ same type
STARD3 p.Ala394Ser Uncertain significance ★ ⚠ same type
STARD3 p.Ala443Ser Uncertain significance ★ ⚠ same type
STARD3 p.Arg105Cys Uncertain significance ★ ⚠ same type
STARD3 p.Arg14Gly Uncertain significance ★ ⚠ same type
STARD3 p.Arg14His Uncertain significance ★ ⚠ same type
STARD3 p.Arg193Cys 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/stard3-p-leu289pro (accessed [today's date]).

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