Is AASS p.Leu742Phe (c.2224C>T) pathogenic?

AASS p.Leu742Phe (c.2224C>T) is classified Uncertain significance in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.1299); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AASS p.Leu742Phe (c.2224C>T)?

AASS p.Leu742Phe (c.2224C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AASS p.Leu742Phe (c.2224C>T) in the general population?

AASS p.Leu742Phe (c.2224C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AASS p.Leu742Phe (c.2224C>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

AASS p.Leu742Phe

c.2224C>T · rs758445857 · VCV2621206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -9.24	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 12	GERP 0.73, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	24.9	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 0.000339% European (non-Finnish) · 4/1,179,824 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,738 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.Leu742Phe
Coding: c.2224C>T
MANE Select: NM_005763
dbSNP: rs758445857
Type: single nucleotide variant
Location: chr7:122081556 (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 742: the 'saccharopine dehydrogenase' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AASS p.Asn34Lys Uncertain significance ★★ ⚠ same condition
AASS p.Asn865Ser Uncertain significance ★★ ⚠ same condition
AASS p.Gly167Cys Uncertain significance ★★ ⚠ same condition
AASS p.His846Arg Uncertain significance ★★ ⚠ same condition
AASS p.Ile491Met Uncertain significance ★★ ⚠ same condition
AASS p.Leu465Val Uncertain significance ★★ ⚠ same condition
AASS p.Ser474Leu Uncertain significance ★★ ⚠ same condition
AASS p.Ser664Pro Uncertain significance ★★ ⚠ same condition

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-leu742phe (accessed [today's date]).

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