Is AASS p.Pro331Leu (c.992C>T) pathogenic?

AASS p.Pro331Leu (c.992C>T) is classified Benign in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-04). AlphaMissense: likely benign (0.087); Ultra-rare (popmax 0.0117%, amr).

How common is AASS p.Pro331Leu (c.992C>T) in the general population?

AASS p.Pro331Leu (c.992C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about AASS p.Pro331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

AASS p.Pro331Leu

c.992C>T · rs149832034 · VCV1611765

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -8.94	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 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	28.7	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 0.0117% Admixed American · 7/60,012 alleles

Filtering AF 0.00892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00836%

Overall 0.0356% 574/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.664%	151
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed Americangrpmax	0.0117%	8,573
European (non-Finnish)	0.0104%	9,594
African / African-American	0.00267%	37,516
East Asian	0.00223%	44,872
South Asian	0.0011%	91,080

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro331Leu
Coding: c.992C>T
MANE Select: NM_005763
dbSNP: rs149832034
Type: single nucleotide variant
Location: chr7:122115125 (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 331: the 'lysine-ketoglutarate reductase' region

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

Similar variants

AASS p.Pro331= Likely benign ★ same residue
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

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-pro331leu (accessed [today's date]).

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