Is RPL35A p.Arg76Pro (c.227G>C) pathogenic?

RPL35A p.Arg76Pro (c.227G>C) is classified Uncertain significance in RPL35A (ClinVar, Single submitter, 1 submitter; last evaluated 2014-09-16). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with Diamond-Blackfan anemia.

What condition is associated with RPL35A p.Arg76Pro (c.227G>C)?

RPL35A p.Arg76Pro (c.227G>C) is associated with Diamond-Blackfan anemia (ClinVar).

How common is RPL35A p.Arg76Pro (c.227G>C) in the general population?

RPL35A p.Arg76Pro (c.227G>C) is absent from gnomAD v4.1 (gnomAD).

How is Diamond-Blackfan anemia inherited?

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

What do computational predictors say about RPL35A p.Arg76Pro (c.227G>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

RPL35A p.Arg76Pro

c.227G>C · rs1720338562 · VCV1788920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Diamond-Blackfan anemia

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic
REVEL	0.761	pathogenic-leaning
SaProt	LLR -15.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 4,802 bp · p 5.1e-05 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: RPL35A
Protein: p.Arg76Pro
Coding: c.227G>C
MANE Select: NM_032263 · reported on NM_000996
dbSNP: rs1720338562
Type: single nucleotide variant
Location: chr3:197954065 (GRCh38)

Full RPL35A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Diamond-Blackfan anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Diamond-Blackfan anemia (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

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/rpl35a-p-arg76pro (accessed [today's date]).

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