Is AASS p.Phe108Ser (c.323T>C) pathogenic?

AASS p.Phe108Ser (c.323T>C) is classified Uncertain significance in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.9524); Very rare (popmax 0.00267%, afr).

How common is AASS p.Phe108Ser (c.323T>C) in the general population?

AASS p.Phe108Ser (c.323T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about AASS p.Phe108Ser (c.323T>C)?

AlphaMissense predicts likely pathogenic (score 0.9524) — an in-silico prediction, not a clinical call.

AASS p.Phe108Ser

c.323T>C · rs201661225 · VCV1306102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9524	likely pathogenic · top 9% in AASS
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000806% 13/1,613,272 alleles · very rare exomes 7/1,461,130 · genomes 6/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,451
European (non-Finnish)	0.000933%	107,237

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.Phe108Ser
Coding: c.323T>C
MANE Select: NM_005763
dbSNP: rs201661225
Type: single nucleotide variant
Location: chr7:122129425 (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 108: the 'lysine-ketoglutarate reductase' region; a β-strand

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-phe108ser (accessed [today's date]).

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