Is AASS p.Pro847Leu (c.2540C>T) pathogenic?

AASS p.Pro847Leu (c.2540C>T) is classified Uncertain significance in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely benign (0.1204); Very rare (popmax 0.0011%, sas).

How common is AASS p.Pro847Leu (c.2540C>T) in the general population?

AASS p.Pro847Leu (c.2540C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AASS p.Pro847Leu (c.2540C>T)?

AlphaMissense predicts likely benign (score 0.1204) — an in-silico prediction, not a clinical call.

AASS p.Pro847Leu

c.2540C>T · rs2150506235 · VCV1439060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1204	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -10.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	26.8	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 0.0011% South Asian · 1/91,080 alleles

Overall 6.84e-05% 1/1,461,866 alleles · very rare

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: AASS
Protein: p.Pro847Leu
Coding: c.2540C>T
MANE Select: NM_005763
dbSNP: rs2150506235
Type: single nucleotide variant
Location: chr7:122077960 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.73 · 9 PDB
Residue 847: the 'saccharopine dehydrogenase' region

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

Similar variants

AASS c.1767-1G>A Pathogenic/Likely pathogenic ★★ same type
AASS p.Arg132His Likely pathogenic ★★ same type
AASS p.Arg132Cys Uncertain significance ★★ ⚠ same type
AASS p.Arg146Trp Uncertain significance ★★ ⚠ same type
AASS p.Asn34Lys Uncertain significance ★★ ⚠ same type
AASS p.Asn865Ser Uncertain significance ★★ ⚠ same type
AASS p.Gln921Arg Uncertain significance ★★ ⚠ same type
AASS p.Gly167Cys 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/aass-p-pro847leu (accessed [today's date]).

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