Is ACTR5 p.Leu415Phe (c.1245G>C) pathogenic?

ACTR5 p.Leu415Phe (c.1245G>C) is classified Uncertain significance in ACTR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1236); Ultra-rare (popmax 0.0253%, afr).

How common is ACTR5 p.Leu415Phe (c.1245G>C) in the general population?

ACTR5 p.Leu415Phe (c.1245G>C) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

What do computational predictors say about ACTR5 p.Leu415Phe (c.1245G>C)?

AlphaMissense predicts likely benign (score 0.1236) — an in-silico prediction, not a clinical call.

ACTR5 p.Leu415Phe

c.1245G>C · rs199604949 · VCV2464844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1236 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1236	likely benign
REVEL	0.455	indeterminate
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.57 · regional, not allelic
Overall
CADD	24.9	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 0.0253% African / African-American · 19/75,034 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00297% 48/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,949
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0022%	45,385
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: ACTR5
Protein: p.Leu415Phe
Coding: c.1245G>C
MANE Select: NM_024855
dbSNP: rs199604949
Type: single nucleotide variant
Location: chr20:38765470 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.75 · 6 PDB

Full ACTR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR5 p.Ala11Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala13Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala14Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala235Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala253Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala371Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala541Gly Uncertain significance ★ ⚠ same type
ACTR5 p.Arg210His 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/actr5-p-leu415phe (accessed [today's date]).

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