Is RET p.Phe299= (c.897C>T) pathogenic?

RET p.Phe299= (c.897C>T) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0117%, amr); Associated with multiple endocrine neoplasia type 2B.

What condition is associated with RET p.Phe299= (c.897C>T)?

RET p.Phe299= (c.897C>T) is associated with multiple endocrine neoplasia type 2B, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Phe299= (c.897C>T) in the general population?

RET p.Phe299= (c.897C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

RET p.Phe299=

c.897C>T · rs529153319 · VCV477390

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

multiple endocrine neoplasia type 2B

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 -6.2	GERP -4
Overall
CADD	5.708	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,998 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0018% 29/1,612,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0032%	31,225
European (non-Finnish)	0.0017%	58,995

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.Phe299=
Coding: c.897C>T
MANE Select: NM_020975
dbSNP: rs529153319
Type: single nucleotide variant
Location: chr10:43106405 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 299: the 'cadherin-like region 3 (cld3)' region

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

Disease context

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

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Phe299Val 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
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-phe299 (accessed [today's date]).

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