Is ACTBL2 p.Ile123Thr (c.368T>C) pathogenic?

ACTBL2 p.Ile123Thr (c.368T>C) is classified Uncertain significance in ACTBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: ambiguous (0.4714); Very rare (popmax 0.00847%, nfe).

How common is ACTBL2 p.Ile123Thr (c.368T>C) in the general population?

ACTBL2 p.Ile123Thr (c.368T>C) is very rare (popmax 0.00847%, nfe) (gnomAD).

What do computational predictors say about ACTBL2 p.Ile123Thr (c.368T>C)?

AlphaMissense predicts ambiguous (score 0.4714) — an in-silico prediction, not a clinical call.

ACTBL2 p.Ile123Thr

c.368T>C · rs199915773 · VCV2353138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00847%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4714	ambiguous
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,127 bp · p 0.086 · regional, not allelic
Overall
CADD	25.2	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 0.00847% European (non-Finnish) · 100/1,180,008 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00694% 112/1,613,778 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00847%	11,800
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00625%	16,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00333%	29,988

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: ACTBL2
Protein: p.Ile123Thr
Coding: c.368T>C
MANE Select: NM_001017992
dbSNP: rs199915773
Type: single nucleotide variant
Location: chr5:57482340 (GRCh38)
Gene constraint: LOEUF 1.624 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.97

Full ACTBL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTBL2 p.Ala171Pro Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala171Ser Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala171Val Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala27Asp Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala296Val Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala30Ser Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala322Thr Uncertain significance ★ ⚠ same type
ACTBL2 p.Arg178Leu 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/actbl2-p-ile123thr (accessed [today's date]).

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