Is CFHR1 p.Ter331Trp (c.992A>G) pathogenic?

CFHR1 p.Ter331Trp (c.992A>G) is classified Conflicting classifications of pathogenicity in CFHR1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). Rare (popmax 0.487%, mid).

How common is CFHR1 p.Ter331Trp (c.992A>G) in the general population?

CFHR1 p.Ter331Trp (c.992A>G) is rare (popmax 0.487%, mid) (gnomAD).

CFHR1 p.Ter331Trp

c.992A>G · rs145057542 · VCV2682698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.487%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -3.6
Overall
CADD	0.618	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.487% Middle Eastern · 26/5,344 alleles

Filtering AF 0.341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.292%

Overall 0.0417% 634/1,521,394 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.487%	206
South Asian	0.14%	715
Remaining individualsnot grpmax-eligible	0.0561%	1,782
Admixed American	0.0535%	1,871
European (non-Finnish)	0.0372%	2,686
African / African-American	0.0136%	7,354
Finnishnot grpmax-eligible	0.00804%	12,443

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: CFHR1
Protein: p.Ter331Trp
Coding: c.992A>G
MANE Select: NM_002113
dbSNP: rs145057542
Type: single nucleotide variant
Location: chr1:196831998 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB

Full CFHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR1 p.Ter331IleextTer? Likely benign ★★ same residue
CFHR1 p.Asp218Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Gln44Ter Uncertain significance ★★ same type
CFHR1 p.Ile214Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Ile70Val Uncertain significance ★★ ⚠ same type
CFHR1 p.Pro223Leu Uncertain significance ★★ ⚠ same type
CFHR1 p.Tyr304Cys Uncertain significance ★★ ⚠ same type
CFHR1 c.253+108G>C Benign ★★ 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/cfhr1-p-ter331trp (accessed [today's date]).

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