Is RHOH p.Ala166= (c.498C>T) pathogenic?

RHOH p.Ala166= (c.498C>T) is classified Likely benign in RHOH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-24). Very rare (popmax 0.005%, amr); Associated with T-cell immunodeficiency with epidermodysplasia verruciformis.

What condition is associated with RHOH p.Ala166= (c.498C>T)?

RHOH p.Ala166= (c.498C>T) is associated with T-cell immunodeficiency with epidermodysplasia verruciformis (ClinVar).

How common is RHOH p.Ala166= (c.498C>T) in the general population?

RHOH p.Ala166= (c.498C>T) is very rare (popmax 0.005%, amr) (gnomAD).

RHOH p.Ala166=

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.498C>T · rs371722683 · VCV1123575

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 -20	GERP -4.4
Overall
CADD	0.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00428% 69/1,614,012 alleles · very rare exomes 63/1,461,860 · genomes 6/152,152 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed Americangrpmax	0.005%	20,002
European (non-Finnish)	0.00483%	20,702
African / African-American	0.00267%	37,454

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala166=
Coding: c.498C>T
MANE Select: NM_004310
dbSNP: rs371722683
Type: single nucleotide variant
Location: chr4:40243884 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 92.81
Residue 166: 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.Ala166Thr 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.Ala170= Benign/Likely benign ★★ same condition
RHOH p.Asp48= Benign/Likely benign ★★ same condition
RHOH p.Asp77= 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-ala166 (accessed [today's date]).

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