Is SOST p.Pro99Ala (c.295C>G) pathogenic?

SOST p.Pro99Ala (c.295C>G) is classified Uncertain significance in SOST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-17). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.00129%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SOST p.Pro99Ala (c.295C>G)?

SOST p.Pro99Ala (c.295C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SOST p.Pro99Ala (c.295C>G) in the general population?

SOST p.Pro99Ala (c.295C>G) is very rare (popmax 0.00129%, nfe) (gnomAD).

What do computational predictors say about SOST p.Pro99Ala (c.295C>G)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

SOST p.Pro99Ala

c.295C>G · rs778302663 · VCV2211834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00129%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.772	pathogenic-leaning
SaProt	LLR -8.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,396 bp · p 0.26 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00129% European (non-Finnish) · 15/1,162,882 alleles

Filtering AF 0.000774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000614%

Overall 0.000959% 15/1,563,468 alleles · very rare exomes 14/1,411,206 · genomes 1/152,262 · joint denominator

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: SOST
Protein: p.Pro99Ala
Coding: c.295C>G
MANE Select: NM_025237
dbSNP: rs778302663
Type: single nucleotide variant
Location: chr17:43755689 (GRCh38)
Gene constraint: LOEUF 1.634 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.73 · 3 PDB
Residue 99: the ctck domain

Full SOST 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

SOST p.Pro99Leu Uncertain significance ★ ⚠ same residue
SOST p.Arg160Pro Uncertain significance ★★ ⚠ same condition
SOST p.Asn117Ser Uncertain significance ★★ ⚠ same condition
SOST p.Gly62Arg Uncertain significance ★★ ⚠ same condition
SOST p.Ala199Ser Uncertain significance ★ ⚠ same condition
SOST p.Ala6Val Uncertain significance ★ ⚠ same condition
SOST p.Arg126Pro Uncertain significance ★ ⚠ same condition
SOST p.Arg188Trp 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/sost-p-pro99ala (accessed [today's date]).

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