Is POC1B p.Pro154Ser (c.460C>T) pathogenic?

POC1B p.Pro154Ser (c.460C>T) is classified Uncertain significance in POC1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-17). AlphaMissense: likely benign (0.2328); Very rare (popmax 0.00336%, afr); Associated with cone-rod dystrophy 20.

What condition is associated with POC1B p.Pro154Ser (c.460C>T)?

POC1B p.Pro154Ser (c.460C>T) is associated with cone-rod dystrophy 20 (ClinVar).

How common is POC1B p.Pro154Ser (c.460C>T) in the general population?

POC1B p.Pro154Ser (c.460C>T) is very rare (popmax 0.00336%, afr) (gnomAD).

How is Cone rod dystrophy inherited?

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

What do computational predictors say about POC1B p.Pro154Ser (c.460C>T)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

POC1B p.Pro154Ser

c.460C>T · rs199977729 · VCV1013706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cone-rod dystrophy 20

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 105 kb · p 0.47 · regional, not allelic
Overall
CADD	25.5	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 0.00336% African / African-American · 2/59,538 alleles

Filtering AF 0.00082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000664%

Overall 0.00128% 20/1,560,680 alleles · very rare exomes 17/1,445,302 · genomes 3/115,378 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00336%	29,769
Remaining individualsnot grpmax-eligible	0.00326%	30,696
European (non-Finnish)	0.00139%	72,159

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: POC1B
Protein: p.Pro154Ser
Coding: c.460C>T
MANE Select: NM_172240
dbSNP: rs199977729
Type: single nucleotide variant
Location: chr12:89472268 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.62

Full POC1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cone-rod dystrophy 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

POC1B p.Pro154= Likely benign ★★ same residue
POC1B c.101-3T>G Pathogenic/Likely pathogenic ★★ same condition
POC1B c.560+2T>G Pathogenic ★★ same condition
POC1B c.676+1G>A Pathogenic/Likely pathogenic ★★ same condition
POC1B c.810+1G>T Pathogenic ★★ same condition
POC1B p.Arg106Pro Pathogenic ★★ ⚠ same condition
POC1B c.1032+4A>G Uncertain significance ★★ same condition
POC1B p.Ala76Val Uncertain significance ★★ ⚠ 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/poc1b-p-pro154ser (accessed [today's date]).

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