Is ARL16 p.Ser76Phe (c.227C>T) pathogenic?

ARL16 p.Ser76Phe (c.227C>T) is classified Uncertain significance in ARL16 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.3423); Very rare (popmax 0.00534%, afr).

How common is ARL16 p.Ser76Phe (c.227C>T) in the general population?

ARL16 p.Ser76Phe (c.227C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ARL16 p.Ser76Phe (c.227C>T)?

AlphaMissense predicts ambiguous (score 0.3423) — an in-silico prediction, not a clinical call.

ARL16 p.Ser76Phe

c.227C>T · VCV3946981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3423	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.048, phastCons 0.062
Regional constraint	o/e 1.12	unconstrained · MANE · 2,042 bp · p 0.081 · regional, not allelic
Overall
CADD	18.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S100F vs ClinVar S76F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,918 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,613,338 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	8.48e-05%	1,179,663

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: ARL16
Protein: p.Ser76Phe
Coding: c.227C>T
MANE Select: NM_001040025
Type: single nucleotide variant
Location: chr17:81683020 (GRCh38)
Gene constraint: LOEUF 1.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.91

Full ARL16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARL16 c.-41G>T Likely pathogenic ★ ⚠ same type
ARL16 c.-20C>A Uncertain significance ★ ⚠ same type
ARL16 c.-3G>A Uncertain significance ★ ⚠ same type
ARL16 p.Ala108Gly Uncertain significance ★ ⚠ same type
ARL16 p.Ala152Thr Uncertain significance ★ ⚠ same type
ARL16 p.Ala167Val Uncertain significance ★ ⚠ same type
ARL16 p.Ala7Pro Uncertain significance ★ ⚠ same type
ARL16 p.Arg153Cys 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/arl16-p-ser76phe (accessed [today's date]).

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