Is MID2 p.Arg253His (c.758G>A) pathogenic?

MID2 p.Arg253His (c.758G>A) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-11-11). AlphaMissense: likely benign (0.2931); Very rare (popmax 0.00592%, eas).

How common is MID2 p.Arg253His (c.758G>A) in the general population?

MID2 p.Arg253His (c.758G>A) is very rare (popmax 0.00592%, eas) (gnomAD).

What do computational predictors say about MID2 p.Arg253His (c.758G>A)?

AlphaMissense predicts likely benign (score 0.2931) — an in-silico prediction, not a clinical call.

MID2 p.Arg253His

c.758G>A · rs200061253 · VCV435870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00592%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2931	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 101 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	26.4	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 0.00592% East Asian · 2/33,812 alleles

Filtering AF 0.00362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00322%

Overall 0.0038% 46/1,210,499 alleles · very rare exomes 46/1,096,961 · genomes 0/113,538 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00592%	16,906
European (non-Finnish)	0.00481%	20,804
Remaining individualsnot grpmax-eligible	0.0021%	47,615

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.Arg253His
Coding: c.758G>A
MANE Select: NM_012216
dbSNP: rs200061253
Type: single nucleotide variant
Location: chrX:107854646 (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.Arg253Cys 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-arg253his (accessed [today's date]).

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