Is RB1 p.Ile172Val (c.514A>G) pathogenic?

RB1 p.Ile172Val (c.514A>G) is classified Uncertain significance in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-01). AlphaMissense: likely benign (0.1437); Very rare (popmax 0.00332%, sas); Associated with retinoblastoma.

What condition is associated with RB1 p.Ile172Val (c.514A>G)?

RB1 p.Ile172Val (c.514A>G) is associated with retinoblastoma, hereditary neoplastic syndrome (ClinVar).

How common is RB1 p.Ile172Val (c.514A>G) in the general population?

RB1 p.Ile172Val (c.514A>G) is very rare (popmax 0.00332%, sas) (gnomAD).

How is Retinoblastoma inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RB1 p.Ile172Val (c.514A>G)?

AlphaMissense predicts likely benign (score 0.1437) — an in-silico prediction, not a clinical call.

RB1 p.Ile172Val

c.514A>G · rs2138091600 · VCV1056846

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00332%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinoblastoma

Computational evidence

Protein change
AlphaMissense	0.1437	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 156 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00332% South Asian · 3/90,286 alleles

Filtering AF 0.000883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000445%

Overall 0.000251% 4/1,594,372 alleles · very rare exomes 4/1,442,242 · genomes 0/152,130 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00332%	30,095
European (non-Finnish)	8.6e-05%	1,163,316

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: RB1
Protein: p.Ile172Val
Coding: c.514A>G
MANE Select: NM_000321
dbSNP: rs2138091600
Type: single nucleotide variant
Location: chr13:48347838 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.03 · 19 PDB
Residue 172: an α-helix

Full RB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinoblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Retinoblastoma (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Childhood, Infancy
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

RB1 p.Ile172Leu Uncertain significance ★★ ⚠ same residue
RB1 p.Ile172Met Uncertain significance ★★ ⚠ same residue
RB1 p.Ile172Thr Uncertain significance ★★ ⚠ same residue
RB1 p.Ile172dup Uncertain significance ★ same residue
RB1 c.1049+1G>A Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1049+1G>T Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1049+3A>G Pathogenic/Likely pathogenic ★★ same condition
RB1 c.1050-2A>G Pathogenic/Likely 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/rb1-p-ile172val (accessed [today's date]).

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