Is AARD p.Pro154Leu (c.461C>T) pathogenic?

AARD p.Pro154Leu (c.461C>T) is classified Likely benign in AARD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.0688); Ultra-rare (popmax 0.0164%, mid).

How common is AARD p.Pro154Leu (c.461C>T) in the general population?

AARD p.Pro154Leu (c.461C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about AARD p.Pro154Leu (c.461C>T)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

AARD p.Pro154Leu

c.461C>T · rs772752976 · VCV3134937

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.04	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 -1.8	GERP -3.7
Regional constraint	o/e 1.12	unconstrained · MANE · 4,454 bp · p 0.076 · regional, not allelic
Overall
CADD	0.098	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 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00428% 69/1,613,190 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,494
East Asian	0.00668%	14,961
South Asian	0.00659%	15,178
Admixed American	0.005%	19,993
European (non-Finnish)	0.00432%	23,133

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: AARD
Protein: p.Pro154Leu
Coding: c.461C>T
MANE Select: NM_001025357
dbSNP: rs772752976
Type: single nucleotide variant
Location: chr8:116942694 (GRCh38)
Gene constraint: LOEUF 1.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.24

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

Similar variants

AARD p.Ala70= Benign ★★ same type
AARD p.Ala82Thr Uncertain significance ★ ⚠ same type
AARD p.Ala82Val Uncertain significance ★ ⚠ same type
AARD p.Ala83Gly Uncertain significance ★ ⚠ same type
AARD p.Ala85Gly Uncertain significance ★ ⚠ same type
AARD p.Arg103Thr Uncertain significance ★ ⚠ same type
AARD p.Asp150Glu Uncertain significance ★ ⚠ same type
AARD p.Gln130Lys 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/aard-p-pro154leu (accessed [today's date]).

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