Is PDE6C p.Thr720Met (c.2159C>T) pathogenic?

PDE6C p.Thr720Met (c.2159C>T) is classified Pathogenic/Likely pathogenic in PDE6C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely pathogenic (0.9667); Very rare (popmax 0.00803%, afr); Associated with PDE6C-related disorder.

What condition is associated with PDE6C p.Thr720Met (c.2159C>T)?

PDE6C p.Thr720Met (c.2159C>T) is associated with PDE6C-related disorder (ClinVar).

How common is PDE6C p.Thr720Met (c.2159C>T) in the general population?

PDE6C p.Thr720Met (c.2159C>T) is very rare (popmax 0.00803%, afr) (gnomAD).

What do computational predictors say about PDE6C p.Thr720Met (c.2159C>T)?

AlphaMissense predicts likely pathogenic (score 0.9667) — an in-silico prediction, not a clinical call.

PDE6C p.Thr720Met

c.2159C>T · rs776912070 · VCV939368

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00803%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PDE6C-related disorder

Computational evidence

Protein change
AlphaMissense	0.9667	likely pathogenic ✓ concordant with ClinVar
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00803% African / African-American · 6/74,764 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00205% 33/1,610,554 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00803%	12,461
East Asian	0.00223%	44,794
South Asian	0.0022%	45,441
European (non-Finnish)	0.00204%	49,116

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: PDE6C
Protein: p.Thr720Met
Coding: c.2159C>T
MANE Select: NM_006204
dbSNP: rs776912070
Type: single nucleotide variant
Location: chr10:93659118 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.53 · 7 PDB
Residue 720: a UniProt-annotated variant site (in achm5); the pdease domain; an α-helix

Full PDE6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PDE6C-related disorder

Similar variants

PDE6C p.Thr720= Likely benign ★★ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.481-1G>A Likely pathogenic ★★ same condition
PDE6C c.939+2T>G Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.939+5G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg104Trp Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg557Ter Pathogenic/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/pde6c-p-thr720met (accessed [today's date]).

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