Is RET p.Ser32Leu (c.95C>T) pathogenic?

RET p.Ser32Leu (c.95C>T) is classified Likely pathogenic in RET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-21). AlphaMissense: likely benign (0.2786); Very rare (popmax 8.47e-05%, nfe); Associated with RET-related disorder.

What condition is associated with RET p.Ser32Leu (c.95C>T)?

RET p.Ser32Leu (c.95C>T) is associated with RET-related disorder, Hirschsprung disease, susceptibility to, 1, Hirschsprung disease (ClinVar).

How common is RET p.Ser32Leu (c.95C>T) in the general population?

RET p.Ser32Leu (c.95C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RET p.Ser32Leu (c.95C>T)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

RET p.Ser32Leu

c.95C>T · rs76764689 · VCV13923

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign ⚠ discordant with ClinVar
REVEL	0.433	indeterminate
SaProt	LLR -5.86	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 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 1,972 bp · p 4.9e-10 · regional, not allelic
Overall
CADD	24.7	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 8.47e-05% European (non-Finnish) · 1/1,180,004 alleles

Overall 6.84e-05% 1/1,461,532 alleles · very rare

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.Ser32Leu
Coding: c.95C>T
MANE Select: NM_020975
dbSNP: rs76764689
Type: single nucleotide variant
Location: chr10:43100480 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 32: a β-strand; a UniProt-annotated variant site (in hscr1; familial form); the 'cadherin-like region 1 (cld1)' region

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

Disease context

RET-related disorder

Also linked: Hirschsprung disease, susceptibility to, 1 Hirschsprung disease multiple endocrine neoplasia type 2

Similar variants

RET p.Ser32= Conflicting classifications of pathogenicity ★ same residue
RET p.Ser32Trp 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.Arg897Gln 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-ser32leu (accessed [today's date]).

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