Is ANKRD53 p.Arg76Ser (c.228G>T) pathogenic?

ANKRD53 p.Arg76Ser (c.228G>T) is classified Uncertain significance in ANKRD53 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-21). AlphaMissense: likely benign (0.1169); Very rare (popmax 0.00891%, nfe).

How common is ANKRD53 p.Arg76Ser (c.228G>T) in the general population?

ANKRD53 p.Arg76Ser (c.228G>T) is very rare (popmax 0.00891%, nfe) (gnomAD).

What do computational predictors say about ANKRD53 p.Arg76Ser (c.228G>T)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

ANKRD53 p.Arg76Ser

c.228G>T · rs1366247408 · VCV3126890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.55	GERP -0.45
Regional constraint	o/e 0.95	unconstrained · MANE · 6,651 bp · p 0.15 · regional, not allelic
Overall
CADD	2.063	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 0.00891% European (non-Finnish) · 105/1,178,998 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00701%

Overall 0.00714% 115/1,610,234 alleles · very rare exomes 113/1,458,008 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,795
European (non-Finnish)grpmax	0.00891%	11,229
East Asian	0.00223%	44,844
Admixed American	0.00167%	59,916

Remaining individuals 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: ANKRD53
Protein: p.Arg76Ser
Coding: c.228G>T
MANE Select: NM_001115116
dbSNP: rs1366247408
Type: single nucleotide variant
Location: chr2:70979154 (GRCh38)
Gene constraint: LOEUF 1.379 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.41
Residue 76: the 'disordered' region

Full ANKRD53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD53 p.Ala11Glu Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala143Asp Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala148Thr Uncertain significance ★ same type
ANKRD53 p.Ala219Ser Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala242Thr Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala310Thr Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala39Pro Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala434Pro Uncertain significance ★ ⚠ 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/ankrd53-p-arg76ser (accessed [today's date]).

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