Is MID2 p.Arg56His (c.167G>A) pathogenic?

MID2 p.Arg56His (c.167G>A) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: ambiguous (0.41); Very rare (popmax 0.00782%, nfe).

How common is MID2 p.Arg56His (c.167G>A) in the general population?

MID2 p.Arg56His (c.167G>A) is very rare (popmax 0.00782%, nfe) (gnomAD).

What do computational predictors say about MID2 p.Arg56His (c.167G>A)?

AlphaMissense predicts ambiguous (score 0.41) — an in-silico prediction, not a clinical call.

MID2 p.Arg56His

c.167G>A · rs373511106 · VCV2339011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.41 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00782%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.41	ambiguous
REVEL	0.652	pathogenic-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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	26.0	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 0.00782% European (non-Finnish) · 70/895,170 alleles

Filtering AF 0.0063% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.00637% 77/1,209,623 alleles · very rare exomes 72/1,098,183 · genomes 5/111,440 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00782%	12,788
African / African-American	0.00526%	19,000
South Asian	0.00352%	28,380
Admixed American	0.00219%	45,706
Remaining individualsnot grpmax-eligible	0.0021%	47,594

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.Arg56His
Coding: c.167G>A
MANE Select: NM_012216
dbSNP: rs373511106
Type: single nucleotide variant
Location: chrX:107840832 (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.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
MID2 p.Arg121Leu 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-arg56his (accessed [today's date]).

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