Is RET p.Leu790Phe (c.2370G>C) pathogenic?

RET p.Leu790Phe (c.2370G>C) is classified Pathogenic/Likely pathogenic in RET (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-10). AlphaMissense: ambiguous (0.4828); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Leu790Phe (c.2370G>C)?

RET p.Leu790Phe (c.2370G>C) is associated with hereditary neoplastic syndrome, familial medullary thyroid carcinoma, multiple endocrine neoplasia type 2A (ClinVar).

How common is RET p.Leu790Phe (c.2370G>C) in the general population?

RET p.Leu790Phe (c.2370G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RET p.Leu790Phe (c.2370G>C)?

AlphaMissense predicts ambiguous (score 0.4828) — an in-silico prediction, not a clinical call.

RET p.Leu790Phe

c.2370G>C · rs75030001 · VCV13935

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.4828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4828	ambiguous
REVEL	0.733	pathogenic-leaning
SaProt	LLR -12.10	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.4	GERP -3.4, phastCons 0.005
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	20.2	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 0.00133% African / African-American · 1/75,070 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000547% 8/1,461,602 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
African / African-Americangrpmax	0.00133%	75,070
European (non-Finnish)	0.000508%	196,663

Remaining individuals 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.Leu790Phe
Coding: c.2370G>C
MANE Select: NM_020975
dbSNP: rs75030001
Type: single nucleotide variant
Location: chr10:43118458 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 790: a UniProt-annotated variant site (in men2a and mtc; familial form); a β-strand; 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: familial medullary thyroid carcinoma multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Leu790= Benign/Likely benign ★★ same residue
RET p.Leu790Ser Uncertain significance ★ ⚠ same residue
RET p.Leu790_Tyr791delinsPheHis Likely pathogenic ★ 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

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-leu790phe (accessed [today's date]).

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