Is APOL5 p.Phe77Leu (c.231T>A) pathogenic?

APOL5 p.Phe77Leu (c.231T>A) is classified Uncertain significance in APOL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: ambiguous (0.3939); Very rare (popmax 0.00593%, nfe).

How common is APOL5 p.Phe77Leu (c.231T>A) in the general population?

APOL5 p.Phe77Leu (c.231T>A) is very rare (popmax 0.00593%, nfe) (gnomAD).

What do computational predictors say about APOL5 p.Phe77Leu (c.231T>A)?

AlphaMissense predicts ambiguous (score 0.3939) — an in-silico prediction, not a clinical call.

APOL5 p.Phe77Leu

c.231T>A · rs769092389 · VCV2459512

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3939	ambiguous · top 9% in APOL5
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.40	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -1.8
Regional constraint	o/e 1.00	unconstrained · MANE · 8,840 bp · p 0.97 · regional, not allelic
Overall
CADD	0.255	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 0.00593% European (non-Finnish) · 70/1,180,046 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00452% 73/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00593%	16,858
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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: APOL5
Protein: p.Phe77Leu
Coding: c.231T>A
MANE Select: NM_030642
dbSNP: rs769092389
Type: single nucleotide variant
Location: chr22:35726299 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 41.66

Full APOL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL5 p.Glu81Lys Benign ★★ same type
APOL5 p.Ala124Glu Uncertain significance ★ ⚠ same type
APOL5 p.Ala141Asp Uncertain significance ★ ⚠ same type
APOL5 p.Ala146Asp Uncertain significance ★ ⚠ same type
APOL5 p.Ala163Glu Uncertain significance ★ ⚠ same type
APOL5 p.Ala197Ser Uncertain significance ★ ⚠ same type
APOL5 p.Ala198Gly Uncertain significance ★ ⚠ same type
APOL5 p.Ala226Thr 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/apol5-p-phe77leu (accessed [today's date]).

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