Is APOH p.Cys23Phe (c.68G>T) pathogenic?

APOH p.Cys23Phe (c.68G>T) is classified Uncertain significance in APOH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9627); Very rare (popmax 8.48e-05%, nfe).

How common is APOH p.Cys23Phe (c.68G>T) in the general population?

APOH p.Cys23Phe (c.68G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about APOH p.Cys23Phe (c.68G>T)?

AlphaMissense predicts likely pathogenic (score 0.9627) — an in-silico prediction, not a clinical call.

APOH p.Cys23Phe

c.68G>T · VCV4127194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9627	likely pathogenic · top 8% in APOH
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -14.04	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 12 kb · p 0.85 · regional, not allelic
Overall
CADD	27.7	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 8.48e-05% European (non-Finnish) · 1/1,179,578 alleles

Overall 6.84e-05% 1/1,461,168 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: APOH
Protein: p.Cys23Phe
Coding: c.68G>T
MANE Select: NM_000042
Type: single nucleotide variant
Location: chr17:66228193 (GRCh38)
Gene constraint: LOEUF 1.542 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.16 · 14 PDB
Residue 23: a disulfide bond; the sushi 1 domain; a β-strand

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

Similar variants

APOH c.64+8C>T Benign ★★ same type
APOH p.Ala160Asp Benign ★★ same type
APOH p.Arg154His Benign ★★ ⚠ same type
APOH p.Asn75Ser Benign ★★ same type
APOH p.Pro53= Benign ★★ same type
APOH p.Ala170Thr Uncertain significance ★ ⚠ same type
APOH p.Ala179Val Uncertain significance ★ ⚠ same type
APOH p.Ala230Thr Uncertain significance ★ ⚠ same type

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/apoh-p-cys23phe (accessed [today's date]).

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