Is EMP2 p.Ala63Val (c.188C>T) pathogenic?

EMP2 p.Ala63Val (c.188C>T) is classified Uncertain significance in EMP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-17). AlphaMissense: likely benign (0.3028); Rare (popmax 0.27%, mid); Associated with nephrotic syndrome, type 10.

What condition is associated with EMP2 p.Ala63Val (c.188C>T)?

EMP2 p.Ala63Val (c.188C>T) is associated with nephrotic syndrome, type 10 (ClinVar).

How common is EMP2 p.Ala63Val (c.188C>T) in the general population?

EMP2 p.Ala63Val (c.188C>T) is rare (popmax 0.27%, mid) (gnomAD).

What do computational predictors say about EMP2 p.Ala63Val (c.188C>T)?

AlphaMissense predicts likely benign (score 0.3028) — an in-silico prediction, not a clinical call.

EMP2 p.Ala63Val

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.188C>T · rs150986636 · VCV2038102

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3028 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.27%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephrotic syndrome, type 10

Computational evidence

Protein change
AlphaMissense	0.3028	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 15 kb · p 0.029 · regional, not allelic
Overall
CADD	22.8	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 0.27% Middle Eastern · 16/5,918 alleles

Filtering AF 0.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.138%

Overall 0.0118% 191/1,613,870 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.27%	370
Ashkenazi Jewishnot grpmax-eligible	0.118%	846
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed American	0.0233%	4,286
African / African-American	0.0227%	4,414
South Asian	0.0176%	5,692
European (non-Finnish)	0.00593%	16,857
East Asian	0.00223%	44,866

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.Ala63Val
Coding: c.188C>T
MANE Select: NM_001424
dbSNP: rs150986636
Type: single nucleotide variant
Location: chr16:10538056 (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.Ala63= Benign ★★ same residue
EMP2 p.Arg166His 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

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-ala63val (accessed [today's date]).

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