Is MID2 p.Arg164His (c.491G>A) pathogenic?

MID2 p.Arg164His (c.491G>A) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-05). AlphaMissense: ambiguous (0.3782); Ultra-rare (popmax 0.0335%, sas); Associated with intellectual disability, X-linked 101.

What condition is associated with MID2 p.Arg164His (c.491G>A)?

MID2 p.Arg164His (c.491G>A) is associated with intellectual disability, X-linked 101 (ClinVar).

How common is MID2 p.Arg164His (c.491G>A) in the general population?

MID2 p.Arg164His (c.491G>A) is ultra-rare (popmax 0.0335%, sas) (gnomAD).

What do computational predictors say about MID2 p.Arg164His (c.491G>A)?

AlphaMissense predicts ambiguous (score 0.3782) — an in-silico prediction, not a clinical call.

MID2 p.Arg164His

c.491G>A · rs778859599 · VCV548625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, sas)

Conditions

intellectual disability, X-linked 101

Computational evidence

Protein change
AlphaMissense	0.3782	ambiguous
REVEL	0.449	indeterminate
SaProt	LLR -6.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 101 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	23.6	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 0.0335% South Asian · 19/56,653 alleles

Filtering AF 0.0219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0043% 52/1,209,093 alleles · ultra-rare exomes 50/1,097,818 · genomes 2/111,275 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0335%	2,982
Middle Eastern	0.0229%	4,373
African / African-American	0.00702%	14,241
Remaining individualsnot grpmax-eligible	0.0042%	23,789
European (non-Finnish)	0.00291%	34,417

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.Arg164His
Coding: c.491G>A
MANE Select: NM_012216
dbSNP: rs778859599
Type: single nucleotide variant
Location: chrX:107841156 (GRCh38)
Structure: AlphaFold pLDDT 80.18 · 4 PDB

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

Disease context

intellectual disability, X-linked 101 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MID2 p.Arg164Gly Uncertain significance ★★ ⚠ same residue
MID2 p.Arg164Cys Uncertain significance ★ ⚠ same residue
MID2 p.Ala150Ser Uncertain significance ★★ ⚠ same condition
MID2 p.Ser60= Benign ★★ same condition
MID2 p.Ile103Ser Uncertain significance ★ ⚠ same condition
MID2 p.Thr125Ala Uncertain significance ★ ⚠ same condition
MID2 p.Arg121His Uncertain significance ★★ ⚠ same type
MID2 p.Thr194= Benign/Likely benign ★★ 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-arg164his (accessed [today's date]).

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