Is SOST p.Phe18Leu (c.52T>C) pathogenic?

SOST p.Phe18Leu (c.52T>C) is classified Uncertain significance in SOST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.4631); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SOST p.Phe18Leu (c.52T>C)?

SOST p.Phe18Leu (c.52T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SOST p.Phe18Leu (c.52T>C) in the general population?

SOST p.Phe18Leu (c.52T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SOST p.Phe18Leu (c.52T>C)?

AlphaMissense predicts ambiguous (score 0.4631) — an in-silico prediction, not a clinical call.

SOST p.Phe18Leu

c.52T>C · VCV4172021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4631	ambiguous
REVEL	0.128	moderately benign-leaning
SaProt	LLR -4.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,396 bp · p 0.26 · regional, not allelic
Overall
CADD	17.61	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,136 alleles · very rare exomes 1/1,461,820 · genomes 0/152,316 · 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.Phe18Leu
Coding: c.52T>C
MANE Select: NM_025237
Type: single nucleotide variant
Location: chr17:43758690 (GRCh38)
Gene constraint: LOEUF 1.634 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.73 · 3 PDB

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.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
SOST p.Arg64Trp 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-phe18leu (accessed [today's date]).

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