Is ANKAR p.Arg519Cys (c.1555C>T) pathogenic?

ANKAR p.Arg519Cys (c.1555C>T) is classified Uncertain significance in ANKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.311); Ultra-rare (popmax 0.0588%, afr).

How common is ANKAR p.Arg519Cys (c.1555C>T) in the general population?

ANKAR p.Arg519Cys (c.1555C>T) is ultra-rare (popmax 0.0588%, afr) (gnomAD).

What do computational predictors say about ANKAR p.Arg519Cys (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.311) — an in-silico prediction, not a clinical call.

ANKAR p.Arg519Cys

c.1555C>T · rs148013275 · VCV2355772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.311	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.66, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 70 kb · p 0.0059 · regional, not allelic
Overall
CADD	27.4	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 0.0588% African / African-American · 44/74,878 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.0031% 50/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0588%	1,702
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed American	0.00167%	59,978
European (non-Finnish)	0.000254%	393,326

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: ANKAR
Protein: p.Arg519Cys
Coding: c.1555C>T
MANE Select: NM_001378068
dbSNP: rs148013275
Type: single nucleotide variant
Location: chr2:189696216 (GRCh38)
Gene constraint: LOEUF 1.07 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79

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

Similar variants

ANKAR p.Asn938= Benign ★★ same type
ANKAR p.Gln1419Leu Benign ★★ same type
ANKAR p.Ile1349= Benign ★★ same type
ANKAR p.Leu94Arg Benign ★★ same type
ANKAR p.Thr206Ala Benign ★★ same type
ANKAR p.Thr92= Benign ★★ same type
ANKAR p.Tyr1262Ser Benign ★★ same type
ANKAR p.Val776Ala 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/ankar-p-arg519cys (accessed [today's date]).

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