Is RDH5 p.Ser73Phe (c.218C>T) pathogenic?

RDH5 p.Ser73Phe (c.218C>T) is classified Conflicting classifications of pathogenicity in RDH5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-20). AlphaMissense: likely pathogenic (0.7506); Very rare (popmax 0.000254%, nfe); Associated with RDH5-related disorder.

What condition is associated with RDH5 p.Ser73Phe (c.218C>T)?

RDH5 p.Ser73Phe (c.218C>T) is associated with RDH5-related disorder (ClinVar).

How common is RDH5 p.Ser73Phe (c.218C>T) in the general population?

RDH5 p.Ser73Phe (c.218C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about RDH5 p.Ser73Phe (c.218C>T)?

AlphaMissense predicts likely pathogenic (score 0.7506) — an in-silico prediction, not a clinical call.

RDH5 p.Ser73Phe

c.218C>T · rs62638185 · VCV8004

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RDH5-related disorder

Computational evidence

Protein change
AlphaMissense	0.7506	likely pathogenic
REVEL	0.654	pathogenic-leaning
SaProt	LLR -15.73	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 6	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 3,357 bp · p 0.041 · regional, not allelic
Overall
CADD	26.4	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,900 alleles · very rare exomes 3/1,461,548 · genomes 0/152,352 · joint denominator

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: RDH5
Protein: p.Ser73Phe
Coding: c.218C>T
MANE Select: NM_002905
dbSNP: rs62638185
Type: single nucleotide variant
Location: chr12:55721402 (GRCh38)
Gene constraint: LOEUF 1.3 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.02
Residue 73: a UniProt-annotated variant site (in falbi; decreased stability; loss of 11-cis retinol dehydrogenase activity; accumulates in the perinuclear region)

Full RDH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RDH5-related disorder

Similar variants

RDH5 p.Gly238Trp Pathogenic/Likely pathogenic ★★ same condition
RDH5 p.Leu24fs Pathogenic ★★ same condition
RDH5 p.Leu272fs Pathogenic/Likely pathogenic ★★ same condition
RDH5 p.Ala26Thr Uncertain significance ★★ ⚠ same type
RDH5 p.Arg191Trp Uncertain significance ★★ ⚠ same type
RDH5 p.Arg251His Uncertain significance ★★ ⚠ same type
RDH5 p.Ser300Ile Uncertain significance ★★ ⚠ same type
RDH5 c.569+54C>T Benign ★★ same type

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/rdh5-p-ser73phe (accessed [today's date]).

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