Is APOL6 p.Arg141Trp (c.421C>T) pathogenic?

APOL6 p.Arg141Trp (c.421C>T) is classified Uncertain significance in APOL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.1566); Ultra-rare (popmax 0.0164%, mid).

How common is APOL6 p.Arg141Trp (c.421C>T) in the general population?

APOL6 p.Arg141Trp (c.421C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about APOL6 p.Arg141Trp (c.421C>T)?

AlphaMissense predicts likely benign (score 0.1566) — an in-silico prediction, not a clinical call.

APOL6 p.Arg141Trp

c.421C>T · rs751750988 · VCV2458797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1566	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -3.2
Regional constraint	o/e 1.02	unconstrained · MANE · 3,167 bp · p 0.67 · regional, not allelic
Overall
CADD	19.7	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00675% 109/1,613,766 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00788%	12,689
Admixed American	0.005%	19,999
African / African-American	0.004%	24,971
East Asian	0.00223%	44,872

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: APOL6
Protein: p.Arg141Trp
Coding: c.421C>T
MANE Select: NM_030641
dbSNP: rs751750988
Type: single nucleotide variant
Location: chr22:35658985 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 54.86

Full APOL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL6 p.Ala161Val Uncertain significance ★ ⚠ same type
APOL6 p.Ala166Pro Uncertain significance ★ ⚠ same type
APOL6 p.Ala181Asp Uncertain significance ★ ⚠ same type
APOL6 p.Ala200Val Uncertain significance ★ ⚠ same type
APOL6 p.Ala263Thr Uncertain significance ★ ⚠ same type
APOL6 p.Ala275Asp Uncertain significance ★ ⚠ same type
APOL6 p.Ala300Ser Uncertain significance ★ ⚠ same type
APOL6 p.Ala5Val 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/apol6-p-arg141trp (accessed [today's date]).

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