Is SI p.Pro83Thr (c.247C>A) pathogenic?

SI p.Pro83Thr (c.247C>A) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely benign (0.2832); Ultra-rare (popmax 0.0145%, sas); Associated with Inborn genetic diseases.

What condition is associated with SI p.Pro83Thr (c.247C>A)?

SI p.Pro83Thr (c.247C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Pro83Thr (c.247C>A) in the general population?

SI p.Pro83Thr (c.247C>A) is ultra-rare (popmax 0.0145%, sas) (gnomAD).

What do computational predictors say about SI p.Pro83Thr (c.247C>A)?

AlphaMissense predicts likely benign (score 0.2832) — an in-silico prediction, not a clinical call.

SI p.Pro83Thr

c.247C>A · rs373958950 · VCV2602028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2832	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -9.88	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 4.7	GERP 0.15, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	20.5	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 0.0145% South Asian · 13/89,356 alleles

Filtering AF 0.0086% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00673%

Overall 0.000936% 15/1,602,900 alleles · ultra-rare exomes 14/1,451,150 · genomes 1/151,750 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0145%	6,874
Remaining individualsnot grpmax-eligible	0.00162%	61,864
European (non-Finnish)	8.52e-05%	1,173,468

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: SI
Protein: p.Pro83Thr
Coding: c.247C>A
MANE Select: NM_001041
dbSNP: rs373958950
Type: single nucleotide variant
Location: chr3:165074539 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 83: the p-type 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SI p.Pro83= Likely benign ★ same residue
SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala760Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ same condition
SI p.Arg1078Gln 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/si-p-pro83thr (accessed [today's date]).

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