Is RET p.Ser556= (c.1668C>G) pathogenic?

RET p.Ser556= (c.1668C>G) is classified Likely benign in RET (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-07). Ultra-rare (popmax 0.036%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser556= (c.1668C>G)?

RET p.Ser556= (c.1668C>G) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Ser556= (c.1668C>G) in the general population?

RET p.Ser556= (c.1668C>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

RET p.Ser556=

c.1668C>G · rs141771814 · VCV261394

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.86	GERP -2, phastCons 1
Overall
CADD	9.814	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/75,050 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0018% 29/1,614,048 alleles · ultra-rare exomes 8/1,461,742 · genomes 21/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,780
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	8.47e-05%	1,179,954

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.Ser556=
Coding: c.1668C>G
MANE Select: NM_020975
dbSNP: rs141771814
Type: single nucleotide variant
Location: chr10:43112872 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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.Ser556Ala 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-ser556 (accessed [today's date]).

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