Is RET p.Pro1067Ser (c.3199C>T) pathogenic?

RET p.Pro1067Ser (c.3199C>T) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.28); Very rare (popmax 0.00935%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Pro1067Ser (c.3199C>T)?

RET p.Pro1067Ser (c.3199C>T) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Pro1067Ser (c.3199C>T) in the general population?

RET p.Pro1067Ser (c.3199C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about RET p.Pro1067Ser (c.3199C>T)?

AlphaMissense predicts likely benign (score 0.28) — an in-silico prediction, not a clinical call.

RET p.Pro1067Ser

c.3199C>T · rs775583354 · VCV543760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.28 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.28	likely benign
REVEL	0.574	indeterminate
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,468 bp · p 0.69 · regional, not allelic
Overall
CADD	26.0	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 0.00935% African / African-American · 7/74,894 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,994 alleles · very rare exomes 5/1,461,860 · genomes 3/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,699
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro1067Ser
Coding: c.3199C>T
MANE Select: NM_020975
dbSNP: rs775583354
Type: single nucleotide variant
Location: chr10:43128123 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 1067: a UniProt-annotated variant site (in a patient with renal agenesis; uncertain significance; prevents phosphorylation in response to gdnf)

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: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Pro1067= Likely benign ★★ same residue
RET p.Pro1067Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro1067ser (accessed [today's date]).

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