Is PDE6A p.Leu671Phe (c.2011C>T) pathogenic?

PDE6A p.Leu671Phe (c.2011C>T) is classified Uncertain significance in PDE6A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 0.00446%, eas); Associated with inherited retinal dystrophy.

What condition is associated with PDE6A p.Leu671Phe (c.2011C>T)?

PDE6A p.Leu671Phe (c.2011C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is PDE6A p.Leu671Phe (c.2011C>T) in the general population?

PDE6A p.Leu671Phe (c.2011C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PDE6A p.Leu671Phe (c.2011C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

PDE6A p.Leu671Phe

c.2011C>T · rs974184621 · VCV3027693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 2% in PDE6A
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -12.70	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 12	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,864 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,459,752 alleles · very rare

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: PDE6A
Protein: p.Leu671Phe
Coding: c.2011C>T
MANE Select: NM_000440
dbSNP: rs974184621
Type: single nucleotide variant
Location: chr5:149884495 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 671: the pdease domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6A p.Leu671= Likely benign ★★ same residue
PDE6A c.1407+1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1926+1G>A Pathogenic ★★ same condition
PDE6A c.627+2T>G Pathogenic ★★ same condition
PDE6A c.998+1G>A Pathogenic ★★ same condition
PDE6A p.Arg102His Pathogenic/Likely pathogenic ★★ same condition
PDE6A p.Arg236Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6A p.Arg257Ter 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/pde6a-p-leu671phe (accessed [today's date]).

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