Is RET p.Val53= (c.159C>T) pathogenic?

RET p.Val53= (c.159C>T) is classified Likely benign in RET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-02). Very rare (popmax 0.000932%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Val53= (c.159C>T)?

RET p.Val53= (c.159C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Val53= (c.159C>T) in the general population?

RET p.Val53= (c.159C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

RET p.Val53=

c.159C>T · rs753523209 · VCV220665

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

hereditary neoplastic syndrome

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 -1.4	GERP -3.4
Overall
CADD	0.416	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,028 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,808 alleles · very rare exomes 10/1,461,596 · genomes 1/152,212 · 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: RET
Protein: p.Val53=
Coding: c.159C>T
MANE Select: NM_020975
dbSNP: rs753523209
Type: single nucleotide variant
Location: chr10:43100544 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 53: the 'cadherin-like region 1 (cld1)' region

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

Disease context

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

Also linked: multiple endocrine neoplasia type 2

Similar variants

RET p.Val53Ile Uncertain significance ★★ ⚠ same residue
RET p.Val53Ala Uncertain significance ★ ⚠ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Ter 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/ret-p-val53 (accessed [today's date]).

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