Is OSTM1 p.Arg85Pro (c.254G>C) pathogenic?

OSTM1 p.Arg85Pro (c.254G>C) is classified Uncertain significance in OSTM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.7288); Ultra-rare (popmax 0.0112%, amr); Associated with Inborn genetic diseases.

What condition is associated with OSTM1 p.Arg85Pro (c.254G>C)?

OSTM1 p.Arg85Pro (c.254G>C) is associated with Inborn genetic diseases (ClinVar).

How common is OSTM1 p.Arg85Pro (c.254G>C) in the general population?

OSTM1 p.Arg85Pro (c.254G>C) is ultra-rare (popmax 0.0112%, amr) (gnomAD).

What do computational predictors say about OSTM1 p.Arg85Pro (c.254G>C)?

AlphaMissense predicts likely pathogenic (score 0.7288) — an in-silico prediction, not a clinical call.

OSTM1 p.Arg85Pro

c.254G>C · rs898484756 · VCV1484633

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7288	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -10.46	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP 0.52, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 20 kb · p 0.83 · regional, not allelic
Overall
CADD	24.4	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 0.0112% Admixed American · 6/53,388 alleles

Filtering AF 0.00483% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00334%

Overall 0.000571% 9/1,576,136 alleles · ultra-rare exomes 5/1,423,914 · genomes 4/152,222 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0112%	8,898
Remaining individualsnot grpmax-eligible	0.00327%	30,552
African / African-American	0.00134%	74,414

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: OSTM1
Protein: p.Arg85Pro
Coding: c.254G>C
MANE Select: NM_014028
dbSNP: rs898484756
Type: single nucleotide variant
Location: chr6:108074398 (GRCh38)
Gene constraint: LOEUF 1.425 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.62 · 9 PDB
Residue 85: an α-helix

Full OSTM1 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

OSTM1 p.Arg144Lys Uncertain significance ★★ ⚠ same condition
OSTM1 p.Arg225Cys Uncertain significance ★★ ⚠ same condition
OSTM1 p.Arg225His Uncertain significance ★★ ⚠ same condition
OSTM1 p.Asn246Ser Uncertain significance ★★ ⚠ same condition
OSTM1 p.Asp81Gly Uncertain significance ★★ ⚠ same condition
OSTM1 p.Glu56Lys Uncertain significance ★★ ⚠ same condition
OSTM1 p.Gly69Ala Uncertain significance ★★ ⚠ same condition
OSTM1 p.Lys311Thr 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/ostm1-p-arg85pro (accessed [today's date]).

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