Is AASS p.Val686Ile (c.2056G>A) pathogenic?

AASS p.Val686Ile (c.2056G>A) is classified Uncertain significance in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0877); Very rare (popmax 0.0072%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AASS p.Val686Ile (c.2056G>A)?

AASS p.Val686Ile (c.2056G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AASS p.Val686Ile (c.2056G>A) in the general population?

AASS p.Val686Ile (c.2056G>A) is very rare (popmax 0.0072%, nfe) (gnomAD).

What do computational predictors say about AASS p.Val686Ile (c.2056G>A)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

AASS p.Val686Ile

c.2056G>A · rs117830956 · VCV2343437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	21.7	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 0.0072% European (non-Finnish) · 85/1,179,744 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00558% 90/1,613,406 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0072%	13,879
African / African-American	0.004%	24,977
Admixed American	0.00167%	59,864
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Val686Ile
Coding: c.2056G>A
MANE Select: NM_005763
dbSNP: rs117830956
Type: single nucleotide variant
Location: chr7:122086140 (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 686: 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

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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-val686ile (accessed [today's date]).

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