Is CPAMD8 p.Phe689Ser (c.2066T>C) pathogenic?

CPAMD8 p.Phe689Ser (c.2066T>C) is classified Uncertain significance in CPAMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely pathogenic (0.9829); Absent from gnomAD v4.1; Associated with anterior segment dysgenesis 8.

What condition is associated with CPAMD8 p.Phe689Ser (c.2066T>C)?

CPAMD8 p.Phe689Ser (c.2066T>C) is associated with anterior segment dysgenesis 8 (ClinVar).

How common is CPAMD8 p.Phe689Ser (c.2066T>C) in the general population?

CPAMD8 p.Phe689Ser (c.2066T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPAMD8 p.Phe689Ser (c.2066T>C)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

CPAMD8 p.Phe689Ser

c.2066T>C · rs2513223376 · VCV2692330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis 8

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic · top 1% in CPAMD8
REVEL	0.725	pathogenic-leaning
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 83 kb · p 0.29 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CPAMD8
Protein: p.Phe689Ser
Coding: c.2066T>C
MANE Select: NM_015692
dbSNP: rs2513223376
Type: single nucleotide variant
Location: chr19:16975101 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.99

Full CPAMD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

anterior segment dysgenesis 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPAMD8 c.2070+1G>A Pathogenic/Likely pathogenic ★★ same condition
CPAMD8 p.Arg1117Ter Likely pathogenic ★★ same condition
CPAMD8 p.Trp178Ter Likely pathogenic ★★ same condition
CPAMD8 p.Asp169Gly Uncertain significance ★★ ⚠ same condition
CPAMD8 c.2070+1G>C Likely pathogenic ★ same condition
CPAMD8 c.3145-1G>T Likely pathogenic ★ same condition
CPAMD8 c.867+2T>G Likely pathogenic ★ same condition
CPAMD8 c.-55G>A 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/cpamd8-p-phe689ser (accessed [today's date]).

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