Is FDFT1 p.Lys45Arg (c.134A>G) pathogenic?

FDFT1 p.Lys45Arg (c.134A>G) is classified Benign/Likely benign in FDFT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0639); Common (popmax 8.22%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with squalene synthase deficiency.

What condition is associated with FDFT1 p.Lys45Arg (c.134A>G)?

FDFT1 p.Lys45Arg (c.134A>G) is associated with squalene synthase deficiency (ClinVar).

What do computational predictors say about FDFT1 p.Lys45Arg (c.134A>G)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

FDFT1 p.Lys45Arg

Q: How common is FDFT1 p.Lys45Arg (c.134A>G) in the general population?

FDFT1 p.Lys45Arg (c.134A>G) is common (popmax 8.22%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.134A>G · rs4731 · VCV1285264

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.22%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

squalene synthase deficiency

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.80	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 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 36 kb · p 1.6e-69 · regional, not allelic
Overall
CADD	19.24	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 8.22% European (non-Finnish) · 97,034/1,179,820 alleles

Filtering AF 8.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.16%

Overall 7.57% 122,178/1,613,782 alleles · common exomes 112,772/1,461,528 · genomes 9,406/152,254 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	17.1%	6
Ashkenazi Jewishnot grpmax-eligible	16.1%	6
Finnishnot grpmax-eligible	8.8%	11
European (non-Finnish)grpmax	8.22%	12
Remaining individualsnot grpmax-eligible	7.7%	13
Middle Eastern	7.37%	14
South Asian	5.86%	17
Admixed American	3.52%	28
African / African-American	1.84%	54
East Asian	1.14%	88

Amish 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: FDFT1
Protein: p.Lys45Arg
Coding: c.134A>G
MANE Select: NM_004462
dbSNP: rs4731
Type: single nucleotide variant
Location: chr8:11808828 (GRCh38)
Gene constraint: LOEUF 1.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.14 · 32 PDB
Residue 45: a UniProt-annotated variant site (influences plasma cholesterol levels; associated with increased total cholesterol and non-high-density lipoprotein cholesterol); an α-helix

Full FDFT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

squalene synthase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FDFT1 c.1033-25T>C Benign ★★ same condition
FDFT1 c.879+9G>C Benign ★★ same condition
FDFT1 p.Leu211= Benign ★★ same condition
FDFT1 p.Leu324= Benign ★★ same condition
FDFT1 p.Leu300Ter Likely pathogenic ★ same condition
FDFT1 p.Trp231Ter Likely pathogenic ★ same condition
FDFT1 c.100-101G>A Uncertain significance ★ same condition
FDFT1 p.Gln224Glu 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/fdft1-p-lys45arg (accessed [today's date]).

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