Is RHAG p.Phe65Ser (c.194T>C) pathogenic?

RHAG p.Phe65Ser (c.194T>C) is classified Pathogenic in RHAG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.894); Absent from gnomAD v4.1; Associated with overhydrated hereditary stomatocytosis.

What condition is associated with RHAG p.Phe65Ser (c.194T>C)?

RHAG p.Phe65Ser (c.194T>C) is associated with overhydrated hereditary stomatocytosis (ClinVar).

How common is RHAG p.Phe65Ser (c.194T>C) in the general population?

RHAG p.Phe65Ser (c.194T>C) is absent from gnomAD v4.1 (gnomAD).

How is Overhydrated hereditary stomatocytosis inherited?

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

What do computational predictors say about RHAG p.Phe65Ser (c.194T>C)?

AlphaMissense predicts likely pathogenic (score 0.894) — an in-silico prediction, not a clinical call.

RHAG p.Phe65Ser

c.194T>C · rs863225468 · VCV218295

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.894 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

overhydrated hereditary stomatocytosis

Computational evidence

Protein change
AlphaMissense	0.894	likely pathogenic ✓ concordant with ClinVar · top 10% in RHAG
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 31 kb · p 0.34 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RHAG
Protein: p.Phe65Ser
Coding: c.194T>C
MANE Select: NM_000324
dbSNP: rs863225468
Type: single nucleotide variant
Location: chr6:49619326 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 8 PDB
Residue 65: a UniProt-annotated variant site (in ohst; enhances monovalent cation leak; decreases ammonium fluxes; highly decreases stom expression; decreases membrane expression; no effect on water permeability); an α-helix

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

Disease context

overhydrated hereditary stomatocytosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Overhydrated hereditary stomatocytosis (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

RHAG p.Phe65Cys Uncertain significance ★ ⚠ same residue
RHAG c.157+1G>A Pathogenic/Likely pathogenic ★★ same condition
RHAG p.His325Arg Uncertain significance ★★ ⚠ same condition
RHAG p.Val270Ile Benign/Likely benign ★★ ⚠ same condition
RHAG p.Gly279Glu Likely pathogenic ★ same condition
RHAG p.Ala287Val Uncertain significance ★ same condition
RHAG p.Ile213Thr Uncertain significance ★ ⚠ same condition
RHAG p.Ile149Met 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/rhag-p-phe65ser (accessed [today's date]).

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