Is ABCA5 p.Pro217Ser (c.649C>T) pathogenic?

ABCA5 p.Pro217Ser (c.649C>T) is classified Uncertain significance in ABCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: ambiguous (0.3759); Ultra-rare (popmax 0.0119%, nfe).

How common is ABCA5 p.Pro217Ser (c.649C>T) in the general population?

ABCA5 p.Pro217Ser (c.649C>T) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

What do computational predictors say about ABCA5 p.Pro217Ser (c.649C>T)?

AlphaMissense predicts ambiguous (score 0.3759) — an in-silico prediction, not a clinical call.

ABCA5 p.Pro217Ser

c.649C>T · VCV4635933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3759	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -2.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.22 · regional, not allelic
Overall
CADD	21.3	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 0.0119% European (non-Finnish) · 140/1,174,544 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00968%

Overall 0.0091% 146/1,603,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,390
Remaining individualsnot grpmax-eligible	0.00323%	30,961
African / African-American	0.00269%	37,188
East Asian	0.00226%	44,182
Finnishnot grpmax-eligible	0.00157%	63,680

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.Pro217Ser
Coding: c.649C>T
MANE Select: NM_172232
Type: single nucleotide variant
Location: chr17:69306864 (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.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
ABCA5 p.Ile1173Val 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-pro217ser (accessed [today's date]).

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