Is ALMS1 p.Arg4146= (c.12438G>T) pathogenic?

ALMS1 p.Arg4146= (c.12438G>T) is classified Conflicting classifications of pathogenicity in ALMS1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0217%, nfe); Associated with Alstrom syndrome.

What condition is associated with ALMS1 p.Arg4146= (c.12438G>T)?

ALMS1 p.Arg4146= (c.12438G>T) is associated with Alstrom syndrome (ClinVar).

How common is ALMS1 p.Arg4146= (c.12438G>T) in the general population?

ALMS1 p.Arg4146= (c.12438G>T) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

How is Alström syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ALMS1 p.Arg4146=

c.12438G>T · rs35902379 · VCV390350

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

Conditions

Alstrom syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.088	GERP -3.7, phastCons 0.12
Overall
CADD	2.613	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% European (non-Finnish) · 256/1,179,950 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0348% 562/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.456%	219
Finnishnot grpmax-eligible	0.233%	430
Remaining individualsnot grpmax-eligible	0.0336%	2,975
European (non-Finnish)grpmax	0.0217%	4,609
African / African-American	0.00133%	74,920

Ashkenazi Jewish 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: ALMS1
Protein: p.Arg4146=
Coding: c.12438G>T
MANE Select: NM_001378454
dbSNP: rs35902379
Type: single nucleotide variant
Location: chr2:73608550 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4146: the 'alms motif' region

Full ALMS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alstrom syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alström syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ALMS1 p.Arg4146Gln Uncertain significance ★★ same residue
ALMS1 p.Arg4146Leu Uncertain significance ★★ same residue
ALMS1 p.Arg4146Trp Uncertain significance ★★ ⚠ same residue
ALMS1 c.10079-1G>C Likely pathogenic ★★ same condition
ALMS1 c.10214-2A>G Likely pathogenic ★★ same condition
ALMS1 c.10384+1G>A Likely pathogenic ★★ same condition
ALMS1 c.10385-2A>G Pathogenic ★★ same condition
ALMS1 c.11547+3A>T Likely pathogenic ★★ 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/alms1-p-arg4146 (accessed [today's date]).

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