Is ANKRD46 p.Pro167Ala (c.499C>G) pathogenic?

ANKRD46 p.Pro167Ala (c.499C>G) is classified Uncertain significance in ANKRD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1471); Very rare (popmax 0.00334%, amr).

How common is ANKRD46 p.Pro167Ala (c.499C>G) in the general population?

ANKRD46 p.Pro167Ala (c.499C>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about ANKRD46 p.Pro167Ala (c.499C>G)?

AlphaMissense predicts likely benign (score 0.1471) — an in-silico prediction, not a clinical call.

ANKRD46 p.Pro167Ala

c.499C>G · VCV3917105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1471	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 7,275 bp · p 6.1e-08 · regional, not allelic
Overall
CADD	26.7	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 0.00334% Admixed American · 2/59,952 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00248% 40/1,613,834 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,976
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00305%	32,778

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: ANKRD46
Protein: p.Pro167Ala
Coding: c.499C>G
MANE Select: NM_001270377
Type: single nucleotide variant
Location: chr8:100522743 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.94

Full ANKRD46 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD46 p.Arg117Cys Uncertain significance ★ ⚠ same type
ANKRD46 p.Arg41His Uncertain significance ★ ⚠ same type
ANKRD46 p.Arg46Lys Uncertain significance ★ ⚠ same type
ANKRD46 p.Asn166Ser Uncertain significance ★ ⚠ same type
ANKRD46 p.Asn97Ser Uncertain significance ★ ⚠ same type
ANKRD46 p.Asp123Asn Uncertain significance ★ ⚠ same type
ANKRD46 p.Asp123Glu Uncertain significance ★ ⚠ same type
ANKRD46 p.Asp59Gly 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/ankrd46-p-pro167ala (accessed [today's date]).

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