Is ARL16 p.Thr125Met (c.374C>T) pathogenic?

ARL16 p.Thr125Met (c.374C>T) is classified Likely benign in ARL16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.0709); Very rare (popmax 0.00356%, nfe).

How common is ARL16 p.Thr125Met (c.374C>T) in the general population?

ARL16 p.Thr125Met (c.374C>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about ARL16 p.Thr125Met (c.374C>T)?

AlphaMissense predicts likely benign (score 0.0709) — an in-silico prediction, not a clinical call.

ARL16 p.Thr125Met

c.374C>T · VCV3430110

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0709	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.36	GERP -4.1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,042 bp · p 0.081 · regional, not allelic
Overall
CADD	1.228	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 T149M vs ClinVar T125M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,179,746 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00279% 45/1,612,762 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,089
African / African-American	0.00267%	37,430
Remaining individualsnot grpmax-eligible	0.0016%	62,436

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.Thr125Met
Coding: c.374C>T
MANE Select: NM_001040025
Type: single nucleotide variant
Location: chr17:81681856 (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-thr125met (accessed [today's date]).

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