Is RET p.Pro320= (c.960C>T) pathogenic?

RET p.Pro320= (c.960C>T) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-18). Ultra-rare (popmax 0.0183%, amr); Associated with multiple endocrine neoplasia type 2A.

What condition is associated with RET p.Pro320= (c.960C>T)?

RET p.Pro320= (c.960C>T) is associated with multiple endocrine neoplasia type 2A, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Pro320= (c.960C>T) in the general population?

RET p.Pro320= (c.960C>T) is ultra-rare (popmax 0.0183%, 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.Pro320=

c.960C>T · rs756761746 · VCV1106240

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

multiple endocrine neoplasia type 2A

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 -14	GERP -4
Overall
CADD	0.627	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,956 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.0013% 21/1,613,300 alleles · ultra-rare exomes 13/1,461,136 · genomes 8/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,451
African / African-American	0.00401%	24,966
South Asian	0.0022%	45,483
European (non-Finnish)	0.000424%	235,955

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.Pro320=
Coding: c.960C>T
MANE Select: NM_020975
dbSNP: rs756761746
Type: single nucleotide variant
Location: chr10:43106468 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 320: 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 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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.Pro320Arg Uncertain significance ★★ ⚠ same residue
RET p.Pro320Ala Uncertain significance ★ ⚠ same residue
RET p.Pro320Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Pro320Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Pro320Thr 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

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-pro320 (accessed [today's date]).

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