Is APOL1 p.Leu385Phe (c.1153C>T) pathogenic?

APOL1 p.Leu385Phe (c.1153C>T) is classified Uncertain significance in APOL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.3388); Ultra-rare (popmax 0.099%, mid).

How common is APOL1 p.Leu385Phe (c.1153C>T) in the general population?

APOL1 p.Leu385Phe (c.1153C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about APOL1 p.Leu385Phe (c.1153C>T)?

AlphaMissense predicts likely benign (score 0.3388) — an in-silico prediction, not a clinical call.

APOL1 p.Leu385Phe

c.1153C>T · rs190804942 · VCV999501

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3388 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3388	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -9.72	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 -0.16	GERP 1.9
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	19.07	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.099% Middle Eastern · 6/6,060 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00143% 23/1,612,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
African / African-American	0.0162%	6,162
Remaining individualsnot grpmax-eligible	0.0048%	20,820
South Asian	0.0011%	90,940
European (non-Finnish)	8.48e-05%	1,179,709

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: APOL1
Protein: p.Leu385Phe
Coding: c.1153C>T
MANE Select: NM_003661
dbSNP: rs190804942
Type: single nucleotide variant
Location: chr22:36265989 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB
Residue 385: the '(microbial infection) required for the interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense' region

Full APOL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL1 p.Ala108Glu Uncertain significance ★★ ⚠ same type
APOL1 p.Ala394Gly Uncertain significance ★★ ⚠ same type
APOL1 p.Arg112Cys Uncertain significance ★★ ⚠ same type
APOL1 p.Asp46Gly Uncertain significance ★★ ⚠ same type
APOL1 p.Gln396Ter Uncertain significance ★★ same type
APOL1 p.Glu110Asp Uncertain significance ★★ ⚠ same type
APOL1 p.Glu323Gln Uncertain significance ★★ ⚠ same type
APOL1 p.His298Arg 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/apol1-p-leu385phe (accessed [today's date]).

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