Is PDE6C p.Thr696Met (c.2087C>T) pathogenic?

PDE6C p.Thr696Met (c.2087C>T) is classified Conflicting classifications of pathogenicity in PDE6C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.102); Rare (popmax 0.677%, mid); Associated with achromatopsia.

What condition is associated with PDE6C p.Thr696Met (c.2087C>T)?

PDE6C p.Thr696Met (c.2087C>T) is associated with achromatopsia, cone dystrophy 4 (ClinVar).

How common is PDE6C p.Thr696Met (c.2087C>T) in the general population?

PDE6C p.Thr696Met (c.2087C>T) is rare (popmax 0.677%, mid) (gnomAD).

How is Achromatopsia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PDE6C p.Thr696Met (c.2087C>T)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

PDE6C p.Thr696Met

c.2087C>T · rs41290222 · VCV879113

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.677%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

achromatopsia

Computational evidence

Protein change
AlphaMissense	0.102	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -12.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.1, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	21.0	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 0.677% Middle Eastern · 41/6,058 alleles

Filtering AF 0.513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.455%

Overall 0.0472% 761/1,612,974 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.677%	148
South Asian	0.235%	426
Admixed American	0.125%	800
Remaining individualsnot grpmax-eligible	0.0752%	1,329
European (non-Finnish)	0.031%	3,222
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,918
African / African-American	0.012%	8,328
East Asian	0.0067%	14,925
Finnishnot grpmax-eligible	0.00156%	63,952

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.Thr696Met
Coding: c.2087C>T
MANE Select: NM_006204
dbSNP: rs41290222
Type: single nucleotide variant
Location: chr10:93658951 (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 696: a UniProt-annotated variant site (in achm5); the pdease domain

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

Disease context

achromatopsia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone dystrophy 4

For Achromatopsia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PDE6C p.Thr696= Likely benign ★ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.1269+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.2283+1G>T Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.939+5G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg259Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg29Trp 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-thr696met (accessed [today's date]).

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