Is PHRF1 p.Pro348Leu (c.1043C>T) pathogenic?

PHRF1 p.Pro348Leu (c.1043C>T) is classified Likely benign in PHRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0334%, amr).

How common is PHRF1 p.Pro348Leu (c.1043C>T) in the general population?

PHRF1 p.Pro348Leu (c.1043C>T) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about PHRF1 p.Pro348Leu (c.1043C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

PHRF1 p.Pro348Leu

c.1043C>T · VCV3417968

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.73	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 -1.9	GERP -3.5
Regional constraint	o/e 1.10	unconstrained · MANE · 30 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	11.8	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 0.0334% Admixed American · 20/59,946 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00632% 102/1,613,412 alleles · ultra-rare exomes 95/1,461,448 · genomes 7/151,964 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.132%	759
Admixed Americangrpmax	0.0334%	2,997
Middle Eastern	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.00961%	10,409
South Asian	0.00659%	15,176
African / African-American	0.00401%	24,941
East Asian	0.00223%	44,882
European (non-Finnish)	0.00212%	47,194

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro348Leu
Coding: c.1043C>T
MANE Select: NM_001286581
Type: single nucleotide variant
Location: chr11:601592 (GRCh38)
Gene constraint: LOEUF 0.573 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 46.11
Residue 348: the 'disordered' region

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

Similar variants

PHRF1 p.Pro348Arg Uncertain significance ★ ⚠ same residue
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

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-pro348leu (accessed [today's date]).

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