Is MOS p.Pro83Leu (c.248C>T) pathogenic?

MOS p.Pro83Leu (c.248C>T) is classified Uncertain significance in MOS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). AlphaMissense: likely benign (0.0756); Ultra-rare (popmax 0.0164%, mid).

How common is MOS p.Pro83Leu (c.248C>T) in the general population?

MOS p.Pro83Leu (c.248C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MOS p.Pro83Leu (c.248C>T)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

MOS p.Pro83Leu

c.248C>T · VCV4552658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -8.10	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 1.7	GERP 0.15, phastCons 0.92
Regional constraint	o/e 0.91	unconstrained · MANE · 1,037 bp · p 0.058 · regional, not allelic
Overall
CADD	18.85	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000744% 12/1,613,740 alleles · ultra-rare exomes 11/1,461,604 · genomes 1/152,136 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.00134%	74,854
European (non-Finnish)	0.000847%	117,996

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: MOS
Protein: p.Pro83Leu
Coding: c.248C>T
MANE Select: NM_005372
Type: single nucleotide variant
Location: chr8:56113735 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 80.98
Residue 83: the protein kinase domain

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

Similar variants

MOS p.Ser182Ter Likely pathogenic ★ same type
MOS p.Ala154Thr Uncertain significance ★ ⚠ same type
MOS p.Ala247Val Uncertain significance ★ ⚠ same type
MOS p.Ala277Glu Uncertain significance ★ ⚠ same type
MOS p.Ala289Thr Uncertain significance ★ ⚠ same type
MOS p.Ala292Val Uncertain significance ★ same type
MOS p.Ala43Thr Uncertain significance ★ ⚠ same type
MOS p.Arg12Leu 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/mos-p-pro83leu (accessed [today's date]).

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