Is RET p.Ser836= (c.2508C>T) pathogenic?

RET p.Ser836= (c.2508C>T) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-02-04). Common (popmax 9.45%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser836= (c.2508C>T)?

RET p.Ser836= (c.2508C>T) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

RET p.Ser836=

Q: How common is RET p.Ser836= (c.2508C>T) in the general population?

RET p.Ser836= (c.2508C>T) is common (popmax 9.45%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2508C>T · rs1800862 · VCV24946

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 23 submitters

gnomAD v4.1

Common

common (popmax 9.45%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

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 1.8	GERP -2.9, phastCons 1
Overall
CADD	10.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.45% South Asian · 8,611/91,086 alleles

Filtering AF 9.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.22%

Overall 4.81% 77,657/1,613,264 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10%	10
South Asiangrpmax	9.45%	11
Middle Eastern	7.28%	14
Ashkenazi Jewishnot grpmax-eligible	5.37%	19
European (non-Finnish)	4.93%	20
Remaining individualsnot grpmax-eligible	4.71%	21
Finnishnot grpmax-eligible	3.58%	28
Admixed American	2.8%	36
African / African-American	2.45%	41
East Asian	0.105%	955

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser836=
Coding: c.2508C>T
MANE Select: NM_020975
dbSNP: rs1800862
Type: single nucleotide variant
Location: chr10:43119646 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 836: the protein kinase domain

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 multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1

Similar variants

RET p.Ser836Asn Uncertain significance ★ ⚠ same residue
RET p.Ser836Cys 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-ser836 (accessed [today's date]).

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