Is MID1 p.Pro166Leu (c.497C>T) pathogenic?

MID1 p.Pro166Leu (c.497C>T) is classified Uncertain significance in MID1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-09). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.00173%, afr).

How common is MID1 p.Pro166Leu (c.497C>T) in the general population?

MID1 p.Pro166Leu (c.497C>T) is very rare (popmax 0.00173%, afr) (gnomAD).

What do computational predictors say about MID1 p.Pro166Leu (c.497C>T)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

MID1 p.Pro166Leu

c.497C>T · VCV4773443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -8.53	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 225 bp · p 7.4e-10 · regional, not allelic
Overall
CADD	23.7	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 0.00173% African / African-American · 1/57,736 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000412%

Overall 0.000908% 11/1,211,826 alleles · very rare exomes 11/1,098,254 · genomes 0/113,572 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00173%	57,736
European (non-Finnish)	0.00112%	89,557

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: MID1
Protein: p.Pro166Leu
Coding: c.497C>T
MANE Select: NM_000381
Type: single nucleotide variant
Location: chrX:10567051 (GRCh38)
Structure: AlphaFold pLDDT 86.51 · 5 PDB

Full MID1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MID1 p.Pro166= Benign/Likely benign ★★ same residue
MID1 p.Ala130Thr Pathogenic/Likely pathogenic ★★ same type
MID1 p.Arg277Ter Pathogenic ★★ same type
MID1 p.Arg368Ter Pathogenic ★★ same type
MID1 p.Arg495Ter Pathogenic ★★ same type
MID1 c.864+4T>G Uncertain significance ★★ same type
MID1 p.Ala114Thr Uncertain significance ★★ ⚠ same type
MID1 p.Ala211Pro 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/mid1-p-pro166leu (accessed [today's date]).

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