Is RHOH p.Ala64= (c.192C>T) pathogenic?

RHOH p.Ala64= (c.192C>T) is classified Likely benign in RHOH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-24). Very rare (popmax 0.00549%, sas); Associated with T-cell immunodeficiency with epidermodysplasia verruciformis.

What condition is associated with RHOH p.Ala64= (c.192C>T)?

RHOH p.Ala64= (c.192C>T) is associated with T-cell immunodeficiency with epidermodysplasia verruciformis (ClinVar).

How common is RHOH p.Ala64= (c.192C>T) in the general population?

RHOH p.Ala64= (c.192C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

RHOH p.Ala64=

Q: How is T-cell immunodeficiency with epidermodysplasia verruciformis inherited?

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

c.192C>T · rs1018020034 · VCV2973877

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

T-cell immunodeficiency with epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -2.4, phastCons 0.99
Overall
CADD	5.512	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,076 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00041% 6/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
European (non-Finnish)	8.47e-05%	1,180,026

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: RHOH
Protein: p.Ala64=
Coding: c.192C>T
MANE Select: NM_004310
dbSNP: rs1018020034
Type: single nucleotide variant
Location: chr4:40243578 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 92.81
Residue 64: a UniProt-annotated variant site (in imd129; loss-of-function variant resulting in impaired t-cell differentiation; unable to rescue t-cell lymphopenia in rhoh knockout mice; no protein detected in patient cells; results in defective tcr signaling in patient cells)

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

Disease context

T-cell immunodeficiency with epidermodysplasia verruciformis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For T-cell immunodeficiency with epidermodysplasia verruciformis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

RHOH p.Ala64Ser Uncertain significance ★ ⚠ same residue
RHOH p.Arg157Gln Uncertain significance ★★ ⚠ same condition
RHOH p.Gly61Ser Uncertain significance ★★ ⚠ same condition
RHOH p.Ser104Gly Uncertain significance ★★ ⚠ same condition
RHOH p.Ala14= Likely benign ★★ same condition
RHOH p.Ala166= Likely benign ★★ same condition
RHOH p.Ala170= Benign/Likely benign ★★ same condition
RHOH p.Asp48= Benign/Likely benign ★★ 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/rhoh-p-ala64 (accessed [today's date]).

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