Is ABCA5 p.Trp45Cys (c.135G>T) pathogenic?

ABCA5 p.Trp45Cys (c.135G>T) is classified Uncertain significance in ABCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: ambiguous (0.4485); Very rare (popmax 0.00576%, afr).

How common is ABCA5 p.Trp45Cys (c.135G>T) in the general population?

ABCA5 p.Trp45Cys (c.135G>T) is very rare (popmax 0.00576%, afr) (gnomAD).

What do computational predictors say about ABCA5 p.Trp45Cys (c.135G>T)?

AlphaMissense predicts ambiguous (score 0.4485) — an in-silico prediction, not a clinical call.

ABCA5 p.Trp45Cys

c.135G>T · rs1184981238 · VCV3103430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, afr)

Computational evidence

Protein change
AlphaMissense	0.4485	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -4.07	tolerated
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Pangolin	Δ0.44	gain · loss 0.32 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.22 · regional, not allelic
Overall
CADD	27.9	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 0.00576% African / African-American · 4/69,454 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.00208% 30/1,438,856 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00731%	13,687
African / African-Americangrpmax	0.00576%	17,363
South Asian	0.00378%	26,463
Admixed American	0.00192%	52,186
European (non-Finnish)	0.00182%	54,943
Remaining individualsnot grpmax-eligible	0.00179%	55,962

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: ABCA5
Protein: p.Trp45Cys
Coding: c.135G>T
MANE Select: NM_172232
dbSNP: rs1184981238
Type: single nucleotide variant
Location: chr17:69313264 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.12

Full ABCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA5 p.Trp45Ser Uncertain significance ★ ⚠ same residue
ABCA5 p.Ser288Phe Uncertain significance ★★ ⚠ same type
ABCA5 c.4765+3A>G Likely benign ★★ same type
ABCA5 p.Asn190Ser Likely benign ★★ ⚠ same type
ABCA5 p.Asn768Asp Benign ★★ same type
ABCA5 p.Asp817Tyr Likely benign ★★ ⚠ same type
ABCA5 p.Gly1159Arg Likely benign ★★ ⚠ same type
ABCA5 p.Gly128= Benign/Likely benign ★★ 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/abca5-p-trp45cys (accessed [today's date]).

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