Is RET p.Ile422= (c.1266C>T) pathogenic?

RET p.Ile422= (c.1266C>T) is classified Likely benign in RET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-27). Ultra-rare (popmax 0.0217%, amr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ile422= (c.1266C>T)?

RET p.Ile422= (c.1266C>T) is associated with multiple endocrine neoplasia type 2, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ile422= (c.1266C>T) in the general population?

RET p.Ile422= (c.1266C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

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

RET p.Ile422=

c.1266C>T · rs759582152 · VCV232505

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.9	GERP -3.7
Overall
CADD	5.729	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/60,006 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00167% 27/1,613,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.0011%	90,764

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.Ile422=
Coding: c.1266C>T
MANE Select: NM_020975
dbSNP: rs759582152
Type: single nucleotide variant
Location: chr10:43111209 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 422: the 'cadherin-like region 4 (cld4)' region

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

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Ile422Met Uncertain significance ★ ⚠ same residue
RET p.Ile422Val Likely benign ★ 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-ile422 (accessed [today's date]).

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