Is AAMDC p.Lys17Glu (c.49A>G) pathogenic?

AAMDC p.Lys17Glu (c.49A>G) is classified Uncertain significance in AAMDC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.0855); Very rare (popmax 0.004%, afr).

How common is AAMDC p.Lys17Glu (c.49A>G) in the general population?

AAMDC p.Lys17Glu (c.49A>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about AAMDC p.Lys17Glu (c.49A>G)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

AAMDC p.Lys17Glu

c.49A>G · VCV3921420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -8.58	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 2.2	GERP -0.11, phastCons 0.97
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	15.0	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 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,974
Admixed American	0.00167%	59,988

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: AAMDC
Protein: p.Lys17Glu
Coding: c.49A>G
MANE Select: NM_024684
Type: single nucleotide variant
Location: chr11:77842545 (GRCh38)
Gene constraint: LOEUF 1.571 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.78 · 2 PDB
Residue 17: the 'mth138-like domain' region

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

Similar variants

AAMDC p.Arg34Trp Uncertain significance ★ ⚠ same type
AAMDC p.Arg69Gln Uncertain significance ★ ⚠ same type
AAMDC p.Glu40Lys Uncertain significance ★ ⚠ same type
AAMDC p.Gly12Glu Uncertain significance ★ ⚠ same type
AAMDC p.Gly18Ala Uncertain significance ★ ⚠ same type
AAMDC p.Gly31Ala Uncertain significance ★ ⚠ same type
AAMDC p.Gly48Arg Uncertain significance ★ ⚠ same type
AAMDC p.Gly61Arg 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/aamdc-p-lys17glu (accessed [today's date]).

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