Is MID2 p.Arg253Cys (c.757C>T) pathogenic?

MID2 p.Arg253Cys (c.757C>T) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.6259); Rare (popmax 0.119%, eas).

How common is MID2 p.Arg253Cys (c.757C>T) in the general population?

MID2 p.Arg253Cys (c.757C>T) is rare (popmax 0.119%, eas) (gnomAD).

What do computational predictors say about MID2 p.Arg253Cys (c.757C>T)?

AlphaMissense predicts likely pathogenic (score 0.6259) — an in-silico prediction, not a clinical call.

MID2 p.Arg253Cys

c.757C>T · VCV4054863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6259 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6259	likely pathogenic
REVEL	0.343	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 0.95, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 101 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	26.7	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 0.119% East Asian · 40/33,755 alleles

Filtering AF 0.0894% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0792%

Overall 0.00463% 56/1,209,068 alleles · rare exomes 47/1,096,949 · genomes 9/112,119 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.119%	844
African / African-American	0.00524%	19,084
Remaining individualsnot grpmax-eligible	0.0021%	47,568
South Asian	0.00176%	56,717
European (non-Finnish)	0.00123%	81,303

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: MID2
Protein: p.Arg253Cys
Coding: c.757C>T
MANE Select: NM_012216
Type: single nucleotide variant
Location: chrX:107854645 (GRCh38)
Structure: AlphaFold pLDDT 80.18 · 4 PDB

Full MID2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MID2 p.Arg253His Uncertain significance ★ ⚠ same residue
MID2 p.Ala150Ser Uncertain significance ★★ ⚠ same type
MID2 p.Arg121His Uncertain significance ★★ ⚠ same type
MID2 p.Arg164Gly Uncertain significance ★★ ⚠ same type
MID2 p.Ser60= Benign ★★ same type
MID2 p.Thr194= Benign/Likely benign ★★ same type
MID2 p.Arg105Pro Uncertain significance ★ ⚠ same type
MID2 p.Arg121Cys 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/mid2-p-arg253cys (accessed [today's date]).

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