Is RET p.Ser696= (c.2088G>A) pathogenic?

RET p.Ser696= (c.2088G>A) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-06-01). Rare (popmax 0.558%, amr); Associated with multiple endocrine neoplasia.

What condition is associated with RET p.Ser696= (c.2088G>A)?

RET p.Ser696= (c.2088G>A) is associated with multiple endocrine neoplasia, Hirschsprung disease, susceptibility to, 1, pheochromocytoma (ClinVar).

How common is RET p.Ser696= (c.2088G>A) in the general population?

RET p.Ser696= (c.2088G>A) is rare (popmax 0.558%, amr) (gnomAD).

RET p.Ser696=

c.2088G>A · rs150329150 · VCV215530

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.558%, amr)

Conditions

multiple endocrine neoplasia

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 -9.9	GERP -3.7
Overall
CADD	0.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.558% Admixed American · 335/59,986 alleles

Filtering AF 0.509% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.49%

Overall 0.0233% 376/1,612,050 alleles · rare exomes 342/1,460,066 · genomes 34/151,984 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.558%	179
Middle Eastern	0.0165%	6,060
African / African-American	0.00667%	14,990
Remaining individualsnot grpmax-eligible	0.0064%	15,624
European (non-Finnish)	0.00254%	39,330
Finnishnot grpmax-eligible	0.00161%	62,254

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.Ser696=
Coding: c.2088G>A
MANE Select: NM_020975
dbSNP: rs150329150
Type: single nucleotide variant
Location: chr10:43114688 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 696: a modified residue (phosphoserine)

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

Disease context

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

Also linked: Hirschsprung disease, susceptibility to, 1 pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1

Similar variants

RET p.Ser696Leu 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-ser696 (accessed [today's date]).

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