Is EMP2 p.Arg166His (c.497G>A) pathogenic?

EMP2 p.Arg166His (c.497G>A) is classified Uncertain significance in EMP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.8229); Ultra-rare (popmax 0.0213%, mid); Associated with nephrotic syndrome, type 10.

What condition is associated with EMP2 p.Arg166His (c.497G>A)?

EMP2 p.Arg166His (c.497G>A) is associated with nephrotic syndrome, type 10 (ClinVar).

How common is EMP2 p.Arg166His (c.497G>A) in the general population?

EMP2 p.Arg166His (c.497G>A) is ultra-rare (popmax 0.0213%, mid) (gnomAD).

What do computational predictors say about EMP2 p.Arg166His (c.497G>A)?

AlphaMissense predicts likely pathogenic (score 0.8229) — an in-silico prediction, not a clinical call.

EMP2 p.Arg166His

Q: How is Hereditary steroid-resistant nephrotic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.497G>A · rs138530114 · VCV1312429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 10

Computational evidence

Protein change
AlphaMissense	0.8229	likely pathogenic
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 15 kb · p 0.029 · regional, not allelic
Overall
CADD	29.8	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 0.0213% Middle Eastern · 1/4,698 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00352% 54/1,535,390 alleles · ultra-rare exomes 44/1,383,398 · genomes 10/151,992 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0213%	4,698
Finnishnot grpmax-eligible	0.00801%	12,490
Remaining individualsnot grpmax-eligible	0.00509%	19,652
East Asian	0.00472%	21,174
European (non-Finnish)	0.00361%	27,711
South Asian	0.00258%	38,734

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: EMP2
Protein: p.Arg166His
Coding: c.497G>A
MANE Select: NM_001424
dbSNP: rs138530114
Type: single nucleotide variant
Location: chr16:10532912 (GRCh38)
Gene constraint: LOEUF 1.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89

Full EMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome, type 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary steroid-resistant nephrotic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

EMP2 p.Ala63Val Uncertain significance ★★ ⚠ same condition
EMP2 p.Tyr143His Uncertain significance ★★ ⚠ same condition
EMP2 c.170-14C>T Benign ★★ same condition
EMP2 c.78+1G>C Likely pathogenic ★ same condition
EMP2 p.Ala10Thr Uncertain significance ★ ⚠ same condition
EMP2 p.Gln62Ter Uncertain significance ★ same condition
EMP2 p.Phe7Leu Pathogenic ⚠ same condition
EMP2 p.Trp29_Val30delinsTer Likely pathogenic ★ same condition

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/emp2-p-arg166his (accessed [today's date]).

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