Is PHRF1 p.Pro1365Ala (c.4093C>G) pathogenic?

PHRF1 p.Pro1365Ala (c.4093C>G) is classified Likely benign in PHRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely benign (0.0502); Ultra-rare (popmax 0.0326%, amr).

How common is PHRF1 p.Pro1365Ala (c.4093C>G) in the general population?

PHRF1 p.Pro1365Ala (c.4093C>G) is ultra-rare (popmax 0.0326%, amr) (gnomAD).

What do computational predictors say about PHRF1 p.Pro1365Ala (c.4093C>G)?

AlphaMissense predicts likely benign (score 0.0502) — an in-silico prediction, not a clinical call.

PHRF1 p.Pro1365Ala

c.4093C>G · rs750919372 · VCV2345271

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0326%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0502	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28
Regional constraint	o/e 1.10	unconstrained · MANE · 30 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	7.673	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 0.0326% Admixed American · 19/58,262 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0177%

Overall 0.00125% 20/1,599,544 alleles · ultra-rare exomes 18/1,447,346 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0326%	3,066
Remaining individualsnot grpmax-eligible	0.00161%	62,048

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: PHRF1
Protein: p.Pro1365Ala
Coding: c.4093C>G
MANE Select: NM_001286581
dbSNP: rs750919372
Type: single nucleotide variant
Location: chr11:609549 (GRCh38)
Gene constraint: LOEUF 0.573 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 46.11
Residue 1365: the 'disordered' region

Full PHRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHRF1 p.Ala1355= Benign ★★ same type
PHRF1 p.Gly1209Arg Benign ★★ same type
PHRF1 p.Ser1168Leu Benign ★★ same type
PHRF1 p.Ser1457Gly Likely benign ★★ same type
PHRF1 p.Thr959= Likely benign ★★ same type
PHRF1 p.Ala114Ser Uncertain significance ★ ⚠ same type
PHRF1 p.Ala114Val Uncertain significance ★ ⚠ same type
PHRF1 p.Ala1197Ser 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/phrf1-p-pro1365ala (accessed [today's date]).

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