Is APOH p.Asn75Ser (c.224A>G) pathogenic?

APOH p.Asn75Ser (c.224A>G) is classified Benign in APOH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-15). AlphaMissense: likely benign (0.1291); Common (popmax 7.22%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about APOH p.Asn75Ser (c.224A>G)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

APOH p.Asn75Ser

Q: How common is APOH p.Asn75Ser (c.224A>G) in the general population?

APOH p.Asn75Ser (c.224A>G) is common (popmax 7.22%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.224A>G · rs138225887 · VCV771498

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.22%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.49, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 12 kb · p 0.85 · regional, not allelic
Overall
CADD	18.26	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 7.22% Admixed American · 4,332/59,970 alleles

Filtering AF 7.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.97%

Overall 0.287% 4,627/1,613,890 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	7.22%	14
Remaining individualsnot grpmax-eligible	0.206%	484
Ashkenazi Jewishnot grpmax-eligible	0.186%	538
African / African-American	0.0453%	2,207
East Asian	0.0379%	2,640
Middle Eastern	0.0165%	6,054
South Asian	0.0165%	6,067
European (non-Finnish)	0.00373%	26,816

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.Asn75Ser
Coding: c.224A>G
MANE Select: NM_000042
dbSNP: rs138225887
Type: single nucleotide variant
Location: chr17:66228037 (GRCh38)
Gene constraint: LOEUF 1.542 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.16 · 14 PDB
Residue 75: a disulfide bond; the sushi 1 domain

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.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
APOH p.Ala333Val 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-asn75ser (accessed [today's date]).

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