Is ACVRL1 p.Phe331Ser (c.992T>C) pathogenic?

ACVRL1 p.Phe331Ser (c.992T>C) is classified Pathogenic in ACVRL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: likely pathogenic (0.9849); Absent from gnomAD v4.1; Associated with telangiectasia, hereditary hemorrhagic, type 2.

What condition is associated with ACVRL1 p.Phe331Ser (c.992T>C)?

ACVRL1 p.Phe331Ser (c.992T>C) is associated with telangiectasia, hereditary hemorrhagic, type 2 (ClinVar).

How common is ACVRL1 p.Phe331Ser (c.992T>C) in the general population?

ACVRL1 p.Phe331Ser (c.992T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACVRL1 p.Phe331Ser (c.992T>C)?

AlphaMissense predicts likely pathogenic (score 0.9849) — an in-silico prediction, not a clinical call.

ACVRL1 p.Phe331Ser

c.992T>C · rs1166311240 · VCV464773

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9849 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

telangiectasia, hereditary hemorrhagic, type 2

Computational evidence

Protein change
AlphaMissense	0.9849	likely pathogenic ✓ concordant with ClinVar
REVEL	0.763	pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 7,154 bp · p 6.9e-20 · regional, not allelic
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACVRL1
Protein: p.Phe331Ser
Coding: c.992T>C
MANE Select: NM_000020
dbSNP: rs1166311240
Type: single nucleotide variant
Location: chr12:51915444 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.51 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.77 · 7 PDB
Residue 331: the protein kinase domain

Full ACVRL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

telangiectasia, hereditary hemorrhagic, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ACVRL1 p.Phe331= Benign/Likely benign ★★ same residue
ACVRL1 p.Arg411Gln Pathogenic ★★★ same condition
ACVRL1 p.Asn98Ser Likely pathogenic ★★★ ⚠ same condition
ACVRL1 p.Cys46Ser Likely pathogenic ★★★ same condition
ACVRL1 p.Cys51Gly Likely pathogenic ★★★ same condition
ACVRL1 p.Cys89Phe Likely pathogenic ★★★ same condition
ACVRL1 p.Gln490Ter Pathogenic ★★★ same condition
ACVRL1 p.Glu236Lys Pathogenic ★★★ same condition

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/acvrl1-p-phe331ser (accessed [today's date]).

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